Seifert et al. BMC Cancer (2022) 22:652 https://doi.org/10.1186/s12885-022-09703-0 RESEARCH Integrative medicine during the intensive phase of chemotherapy in pediatric oncology in Germany: a randomized controlled trial with 5-year follow up Georg Seifert1* , Sarah B. Blakeslee1, Gabriele Calaminus2,3, Farid I. Kandil1, Andrea Barth4, Toralf Bernig5, Carl Friedrich Classen6, Selim Corbacioglu7, Jürgen Föll7, Sven Gottschling8, Bernd Gruhn9, Claudia vom Hoff‑Heise1, Holger N. Lode10, David Martin11,12, Michaela Nathrath13,14, Felix Neunhoeffer15, Arnulf Pekrun16, Beate Wulff17, Tycho Zuzak17,18, Günter Henze1 and Alfred Längler18,19 Abstract Background: Integrative medicine is used frequently alongside chemotherapy treatment in pediatric oncology, but little is known about the influence on toxicity. This German, multi‑center, open‑label, randomized controlled trial assessed the effects of complementary treatments on toxicity related to intensive‑phase chemotherapy treatment in children aged 1–18 with the primary outcome of the toxicity sum score. Secondary outcomes were chemotherapy‑ related toxicity, overall and event‑free survival after 5 years in study patients. Methods: Intervention and control were given standard chemotherapy according to malignancy & tumor type. The intervention arm was provided with anthroposophic supportive treatment (AST); given as anthroposophic base medi‑ cation (AMP), as a base medication for all patients and additional on‑demand treatment tailored to the intervention malignancy groups. The control was given no AMP. The toxicity sum score (TSS) was assessed using NCI‑CTC scales. Results: Data of 288 patients could be analyzed. Analysis did not reveal any statistically significant differences between the AST and the control group for the primary endpoint or the toxicity measures (secondary endpoints). Furthermore, groups did not differ significantly in the five‑year overall and event‑free survival follow up. Discussion: In this trial findings showed that AST was able to be safely administered in a clinical setting, although no beneficial effects of AST between group toxicity scores, overall or event‑free survival were shown. Keywords: Pediatric oncology trial, Anthroposophic medicine, Mistletoe, Complementary cancer treatment, RCT , Randomized controlled trial © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Introduction Background Integrative medicine is used in up to 70% of adult oncol- ogy cases [1] and up to a third of pediatric oncology patients in Germany have been found to use some form of integrative therapy during cancer treatment [2]. Of pediatric patients in oncological treatment who also use integrative therapy, a broad survey with users found that Open Access *Correspondence: georg.seifert@charite.de 1 Department of Pediatrics, Division of Oncology and Hematology, Charité ‑ Universitätsmedizin Berlin, Berlin, Germany Full list of author information is available at the end of the article https://orcid.org/0000-0002-7109-9277 http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/ http://crossmark.crossref.org/dialog/?doi=10.1186/s12885-022-09703-0&domain=pdf Page 2 of 11Seifert et al. BMC Cancer (2022) 22:652 anthroposophic supportive treatment (AST) was used by a third of patients in German pediatric oncological units [3]. Deriving from an alternative-holistic medical tradi- tion developed by Steiner and Wegman in the 1920s that is well-established in Germany and in Europe, anthro- posophic medicinal products (AMP) are used in cancer treatment for symptom management, to achieve a stable condition, to improve the tolerability of standard chem- otherapy and improve the quality of life (QoL) [4]. AMP in pediatric oncology consist of a range of plant and animal-based tinctures, globules, extracts, injections, and compresses [3]. Mistletoe, given in oral and inject- able form, is the most frequently used AMP in oncology and has demonstrated some benefit [5, 6]. Despite a cen- tury of AST for oncological patients such as mistletoe, the effect of treatments given in conjunction with stand- ard chemotherapy is not well-studied in oncology and even less so in pediatric oncology. Evaluated exceptions have shown that in particular, children may benefit from AST interventions [3, 7]. The small body of research that does exist in pediatric oncology using AST has featured case studies highlighting safety [8–10] and quality of life for the young person [11, 12] rather than results of planned clinical trials. Parents of children suffering from intensive chemotherapy view AST as a possible means of assisting their child through difficult circumstances, but at the same time, the potential side effects of AST necessitate better monitoring clinical trials [2, 13]. This study is the first randomized controlled trial in pediat- ric oncology to systematically compare the toxicity of chemotherapy and survival in a 5-year follow up with or without an add-on AST intervention during intensive chemotherapy. Objective and hypothesis including 5‑year follow up data This study investigated the influence of the AST concept on the chemotherapy-associated toxicity in a randomized clinical trial undertaken at 12 German pediatric oncol- ogy clinics. The trial, consisting of an AST intervention, compared an application of AMP in pediatric oncology patients aged 1–18 undergoing standard chemotherapy to the control without AMP. A base of 8 AMP plus 11 on-demand, indication-related on-demand AMP were administered in the intervention group during the inten- sive chemotherapy phase. The trial tested the hypothesis that the AST would reduce the toxicity sum score for pediatric oncology patients undergoing standard treat- ment. The study documented long term changes with 5-year follow up data. The trial’s primary objective inves- tigated the influence of the AST on the chemotherapy- associated toxicity measured by means of a toxicity sum score for hematology, mucositis, general condition and infection using NCI-CTC scales and the overall safety in terms of overall survival (OS) and event-free survival (EFS) until the end of the 5-year follow up. The secondary objective of the study was to investigate any decrease in chemotherapy-associated toxicity. Methods Trial design This clinical trial investigated the effect of the AST for children undergoing chemotherapy combined with standard clinical care from 2005 to 2013 at 12 tertiary-level pediatric care units throughout Ger- many in a prospective, open-label, individually-rand- omized, controlled, national clinical study with parallel group design (Table  1: Inclusion & Exclusion Crite- ria Anthroposophic Supportive Therapy Study). The Institutional Review Board of Charité - Universitäts- medizin Berlin approved the trial as the responsible ethics committee (EA2/141/05). The study was regis- tered at the European Union (EU) Drug Clinical Trials Register (EudraCT- No: 2004–002711-83) [14] before its commencement. All participants provided written informed consent in accordance to the Declaration of Helsinki [15]. Three approved amendments were made to the origi- nal study protocol after commencement of the study and registered once the need for changes became apparent. These included necessary changes made to the inclusion of new and updated chemotherapy protocols, essential adjustments to administered treatments, necessary revi- sion of study administration and modifications to inclu- sion/exclusion specifications. Study recruitment Patients aged 1–18 with planned chemotherapy with a histologically and/or immunologically confirmed pediatric malignancy according to the current stand- ardized treatment protocol were regarded eligible for trial recruitment and recruited from one of the 12 participating tertiary pediatric oncology units if the written consent was given. At the baseline, age, gen- der, educational background and familial situation was recorded for both groups. Sample size was determined based on the intention to decrease the NCI-CTC scale sum score of 2.1 obtained in the ALL-BFM-2000 study [16] by a clinically important difference of 10% to 1.9 in the intervention group (SD = 0.6, alpha = 0.05, Power = 80%). Study intervention Patients of the intervention group only were given the AST regimen as an add-on therapy to standard chemo- therapy treatment (see Fig. 1: Trial Design for the Pediat- ric Anthroposophic Supportive Treatment). Page 3 of 11Seifert et al. BMC Cancer (2022) 22:652 The AST consisted of base AMP including Helixor®, and on-demand supplementary AMP given as needed for symptoms (summary in Table  2: Anthroposophic Sup- portive Treatment Base Medicinal Products and Sup- plementary Table). The control group received standard chemotherapy treatment without additional measures. Administration of the AST intervention and chemo- therapy protocol were tailored for each type of pediat- ric malignancy included in the trial. This included both the base and the on-demand AMP, which were admin- istered based on acute symptoms during intensive chemotherapy. The intervention group started the AST between the day of randomization and day 10 of the first chemotherapy cycle. Study randomization Randomization was centrally allocated at the study headquarters (Charité) by trial administrators (GS, CHH) into intervention and control group by a com- puter supported standard operating procedure that used a combination of unique code identifier and abbreviation for the chemotherapy treatment. Table 1 Inclusion & exclusion criteria anthroposophic supportive therapy study Inclusion Criteria: • Age between 1 year and 18 years • Morphologically and/or immunologically • confirmed diagnosis of a following disease: ○ Hodgkin’s disease (EuroNET‑PHL‑C1) ○ Acute lymphoblastic leukemia (ALL); ○ (ALL‑ BFM 2000; ALL‑BFM 2000 incl. EsPhALL) ○ ALL (COALL 07‑03) ○ Relapse of ALL (ALL‑Rez BFM 2002) ○ Acute myeloid leukemia (AML) (AML‑BFM 2004) ○ Nephroblastoma (SIOP 2001 / GPOH) ○ Germ cell tumors MAKEI 96 ○ Mature B‑NHL / B‑ALL (B‑NHL ‑ BFM 04; B‑ NHL BFM Rituximab) ○ Lymphoblastic lymphoma (until 06/2008 Euro‑LB‑02; from 07/2008 NHL‑BFM 90) ○ Medulloblastoma / PNET or Ependymoma (HIT 2000) ○ Brain tumors‑highly malignant (gliomas HIT‑GBM‑D; until 05/2009) ○ Neuroblastoma (NB 2004 and NB 2004 HR) ○ Osteosarcoma (EURAMOS 1) ○ Ewing’s sarcoma (until 09/2009 EURO‑ E.W.I.N.G ’99; from 10/2009 EWING 2008) ○ Rhabdomyosarcoma (CWS 2002P; until 6/2009) • Protocol‑compliant therapy for the included diseases • Treatment in one of the study centers • Patients must be available during the treatment period and be able to comply with the study plan • Written consent for participation from the patient or the legal guardian Exclusion Criteria: • Serious pre‑existing/ co‑existing psychiatric illness • Other existing serious medical condition that could interfere with the patient’s ability to receive trial‑ appropriate therapy • Any other condition or therapy that, in the opinion of the treating physician, could pose a risk to the patient or interfere with the objectives of the study • Absence of or incomplete informed consent form • Known allergies to any component of the study medications • Pregnancy or not using effective contraception (hormonal contraception, barrier) • Other experimental treatment during or within this study (including chemotherapeutic drugs or immunotherapies not listed in the protocol) Fig. 1 Trial design for the pediatric anthroposophic supportive treatment Page 4 of 11Seifert et al. BMC Cancer (2022) 22:652 Ta bl e 2 A nt hr op os op hi c su pp or tiv e tr ea tm en t b as e m ed ic in al p ro du ct s N am e, D os ag e Fo rm M an uf ac tu re r In gr ed ie nt In di ca tio n A pp lic at io n A dm in is tr at io n an d do se H el ix or ® A 0. 1 m g, 1 m g, 5 m g, 1 0 m g, 2 0 m g, 50 m g, So lu tio n fo r i nj ec tio n H el ix or H ei lm itt el G m bH A qu eo us fr es h pl an t e xt ra ct o f Vi sc um a lb um s ub sp ec ie s ab ie tis , (fi r m is tle to e) M al ig na nt d is ea se Su bc ut an eo us in je ct io n 2x w ee k, d os e in cr ea se d ep en de nt on s ki n re ac tio n: 0 .1 m g – 10 0 m g A ur um /P ru nu s, Li qu id d ilu tio n fo r in je ct io n W A LA H ei lm itt el G m bH Au ru m m et al lic um d il. D 9; P ru nu s sp in os a e flo rib us e t s um m ita tib us fe rm 3 3d d il. D 5 (H A B, M et ho d 33 d) A ur um : P ro te ct io n an d sh ea th fo r th e liv in g or ga ni sm Pr un us : S tr en gt he ni ng o f t he im m un ol og ic al d ef en se In tr av en ou s in je ct io n 1 m l a m pu le g iv en b ef or e ch em o‑ th er ap y N ux v om ic a D 4, S ol ut io n fo r in je ct io n W el ed a A G N ux v om ic a D il. D 4 Fo r f un ct io na l g as tr oi nt es tin al di so rd er s w ith n au se a an d/ or vo m iti ng In tr av en ou s in je ct io n 1 m l a m pu le g iv en b ef or e ch em o‑ th er ap y C ic ho riu m p la nt a to ta 5 % , G lo b‑ ul es W A LA H ei lm itt el G m bH Ci ch or iu m in ty bu s e p la nt a to ta fe rm 33 c (c hi co ry , H A B, M et ho d 33 c) St im ul at io n of rh yt hm ic al ly m ed i‑ at ed p ro ce ss es in th e or ga ni sm in te rm s of h ar m on iz at io n O ra l < 4 ye ar s: 3 × 5 g lo bu le s da ily ≥ 4 ye ar s: 3 × 7 g lo bu le s da ily O xa lis F ol iu m R h D 4, A qu eo us di lu tio n W el ed a A G O xa lis , F ol iu m R h D il. D 4 St im ul at io n an d ha rm on iz at io n of m et ab ol ic p ro ce ss es , a s w el l a s ex cr et or y an d di ge st iv e fu nc tio ns O ra l < 4 ye ar s: 3 × 5 d ro ps d ai ly ≥ 4 ye ar s: 3 × 7 d ro ps d ai ly Ph os ph or us D 8, G lo bu le s W A LA H ei lm itt el G m bH Ph os ph or us d il. D 8 St re ng th en in g of re ge ne ra tiv e fo rc es p lu s ha rm on iz at io n of s le ep ‑ w ak e‑ cy cl e O ra l < 4 ye ar s: 5 gl ob ul es d ai ly in th e m or ni ng ≥ 4 ye ar s: 10 g lo bu le s da ily in th e m or ni ng Ph os ph or us D 30 , G lo bu le s W A LA H ei lm itt el G m bH Ph os ph or us d il. D 30 St re ng th en in g of re ge ne ra tiv e fo rc es p lu s ha rm on iz at io n of s le ep ‑ w ak e‑ cy cl e O ra l < 4 ye ar s: 5 gl ob ul es d ai ly in th e ev en in g ≥ 4 ye ar s: 10 g lo bu le s da ily in th e ev en in g Ra ta nh ia c om p. , S ol ut io n W el ed a A G M yr rh ae ti nc tu ra , R at an hi ae ra di x ex tr ac tu m fl ui du m , A es cu lu s, Co rt ex , et ha no l. D ec oc tu m D il. D 19 , A rg en - tu m n itr ic um D il. D 14 , F lu or it D il. D 9, Ki es er it D il. D 19 , C ar yo ph yl li flo ris ae th er ol eu m , E uc al yp ti ae th er ol eu m , La va nd ul ae a et he ro le um , M en th ae pi pe rit ae a et he ro le um , S al vi ae offi ci na lis a et he ro le um O ra l c ar e du rin g ch em ot he ra py an d in c as e of m an ife st m uc os al le si on s M ou th w as h 30 d ro ps d ai ly in 1 00 m l w at er Page 5 of 11Seifert et al. BMC Cancer (2022) 22:652 Results Sample description A total of 556 patients were screened for eligibility at the 12 trial sites between September 2005 and Novem- ber 2013 (cf. Fig.  2: Anthroposophic Supportive Treat- ment Trial Consort Chart). Of these, 340 were found eligible, sorted into their diagnosis groups and then ran- domized. Reasons for ineligibility in the study were often due to necessary expediency of treatment or complexity of individual clinical cases that complicated study inclu- sion. After accounting for 52 (31 intervention, 21 control) dropouts, 288 patients were included in the intention-to- treat analysis (ITT), of which 216 patients completed all observational visits and administered at least 75% of the base study medications and could thus be included also in the per-protocol analysis (PP). Demographic and clinical parameters of the patient groups can be found in Table  3: Baseline Fig. 2 Anthroposophic supportive treatment trial consort chart Table 3 Baseline characteristics ITT Population PP Population Intervention group Control group Total Intervention group Control group Total Count (n) 139 149 288 82 134 216 Sex: Female 51 (36.7%) 58 (38.9%) 109 (37.8%) 35 (42.7%) 50 (37.3%) 85 (39.4%) Sex: Male 88 (63.3%) 91 (61.1%) 179 (62.2%) 47 (57.3%) 84 (62.7%) 131 (60.6%) Weight [kg] Range 34.5 (8–110) 32.4 (8–92) 33.4 (8–110) 35.0 (10–92) 32.7 (9–110) 33.5 (9–110) Study treatment duration 10.1 months (±8.10) Page 6 of 11Seifert et al. BMC Cancer (2022) 22:652 Characteristics. Baseline age, gender, educational background and familial situation in both groups were similar: About 62% of patients were male, average age in the intervention group was 8 years, while averaged 7.5 years in the control. The intervention group body- weight averaged 35 kg and 32 kg in the control. Patients suffering from an acute lymphoblastic leu- kemia (ALL) by far made up for the largest group with approximately 54% (154 / 288 ITT and 117 / 216 PP patients). Only a minor fraction had previous illnesses (< 15%). Primary outcome: the toxicity sum score (TSS) The underlying data for the custom-defined Tox- icity Sum Score (TSS) was available for 279 of the 288 ITT (96.9%) and for 208 of the 216 PP patients (96.3%). In the ITT analysis, the mean TSS was slightly higher in the intervention group (12.1 ± 3.92, median = 11.6) than in the control group (11.8 ± 4.54, median = 10.9), but slightly lower in the PP analysis (11.4 ± 3.58, median = 11.4 in the intervention group vs. 11.5 ± 4.33, median = 10.7 in the control group). Neither of these differences became statistically sig- nificant in the Mann-Whitney-U-Test, with p = 0.257 and p = 0.716 for the ITT and PP analysis, respec- tively (Fig.  3: Toxicity Sum Score (TSS) Primary Outcome). Secondary outcome: determination of chemotherapy‑associated toxicity Analysis of 43 additional toxicity criteria on the effect of AMP on other chemotherapy-related toxicity found a statistically significant reduction in number of diar- rhea episodes in the intervention group (ITT p = 0.054; Mann-Whitney-U-test and PP- intervention group with p = 0.044, Mann-Whitney-U-test). However, there was no statistical significance for any other second- ary outcome toxicity parameter in either the ITT or PP population. Adverse events Adverse events were only recorded, and thus only ana- lyzed, for the patients in the intervention group (initially 170 patients) who had self-administered at least one of the AMPs during the observational period (n = 163). All in all, 607 AE were documented in 123 patients, among them 532 (87.6%) with secured (n = 472), probable (n = 7), possible (n = 49) or undecidable (n = 4) causal relationship to the treatments. The majority of the cases with secured causality, i.e. 447 cases observed in 105 patients, were accounted for by local inflammations at the injection site after subcutane- ous administration of Helixor® A with a diameter of 5 cm and more. While local reactions from 2 to 5 cm in diam- eter are expected and even desired in mistletoe therapy, reactions with diameters of more than 5 cm are regarded Fig. 3 Toxicity Sum Score (TSS) primary outcome Page 7 of 11Seifert et al. BMC Cancer (2022) 22:652 as AE by the study protocol and thus documented. All other AE were related to the remaining products and were only observed in single cases. Serious adverse events In contrast to AE, Serious Adverse Events SAE were recorded for the intervention and the control group. In total, 15 SAE in 11 patients were recorded for the main study period. Thorough evaluation by the study manage- ment and the Data and Safety Monitoring Committee (DSMC) showed that all SAE were related to chemother- apy-associated toxicities and not to the additional AST and were thus assessed as mislabeled records in the sense of the study protocol. Three of the misrepresented SAE had a lethal outcome with sepsis. Two were in the inter- vention group: one with fulminant sepsis with lethal out- come and the other with fulminant sepsis with absolute neutropenia and presumption diagnosis of intestinal perforation; these had no determined causal relation- ship with the intervention study medication. The third SAE occurred in the control group. According to the assessment of the study management, the cause for these SAE stemmed from the chemotherapy with which these patients were treated. Outcome of five‑year follow up on event‑free and overall survival & safety Overall survival rates (OS) and events-free survival rates (EFS) were based on the intention-to-treat population (288 patients). For the analysis, data of patients in 12 groups with comparable chemotherapy were evaluated (upper half of Fig. 2). None of them showed a statistically significant difference according to the log-rank test, when Bonferroni correction was applied for multiple testing (alpha* = 0.0045). In the remaining six groups (ALL oth- ers, COALL Non-HR, Non-Hodgkin-Lymphoma, glio- blastoma, germ cell tumor, nephroblastoma), no survival data analysis (log-rank test) could be applied because only one or no patient had died in the group. Event-free survival rates (EFS) did not reveal any sta- tistically significant differences between the two groups (lower half of Table 4). Discussion This randomized controlled clinical trial investigated the efficacy and safety of an anthroposophic supportive therapy concept consisting of 19 investigational medici- nal products, applied as a base and on-demand therapy in addition to standard chemotherapy treatment in chil- dren with cancer. For the primary efficacy parameter, the toxicity sum score found no advantage for administration of the anthroposophic supportive therapy that could be demonstrated. Further NCI-CTC toxicity index scores to analyze secondary efficacy parameters only showed an advantage for the administration of the supportive ther- apy in the reduction of the toxicity index score for diar- rhea in the PP-population. In the long term follow up, the explorative analysis of the data available for the 5-year follow up found no indications that efficacy of chemo- therapy was influenced by AST. For long-term toxicities there were also no indications of an influence of AST. The AST-concept can be considered as safe in the long-term observation. Trial findings confirmed that AST was able to be safely administered in a clinical setting. Overall, the analysis of AE including clinical experiences did not reveal any evidence of safety concerns with respect to the adminis- tration of the anthroposophic supportive therapy. Addi- tionally, results of this study found no concerns of the compatibility of anthroposophic supportive therapy with the chemotherapy. This study demonstrated that the administration of the anthroposophic supportive therapy did not disrupt or delay therapy application in the inter- vention group, which is a crucial precondition for effec- tive administration of chemotherapy. This study showed the feasibility of conducting a high- quality, digitally-centralized randomized, scientific evalu- ation of an integrative therapy at multiple centers in the pediatric oncology setting. To our knowledge, there has only been one published comparable randomized study of an integrative therapy in pediatric oncology [17]. A strength of this first randomized controlled trial of a com- plementary anthroposophic treatment to be conducted within pediatric oncology demonstrated the safety of the intervention, the most critical overall outcome. This is comparable to findings in other randomized studies with adults [18, 19]. Additionally, the trial was conducted with a high methodological standard with centralized digital data management and inclusion of multiple centers, and provided long term follow up of the intervention effects. Limitations Limitations, however, should also be mentioned. The complexity of the range of base and on-demand AMP necessitated clearer application guidelines at the study outset that may have permitted more extensive use in symptom treatment. This, on the other hand was difficult to tailor to individual participant tumor entities given the heterogeneity of malignancies included in the trial. While other studies have reached the conclusion of a weak evidence base for single substance efficacy such as with viscum album (mistletoe) given in oncology trials with adults [5], marked quality of life factors have still been found to improve [18, 20]. As one of the success stories in oncology, adjustments to treatment dosages and schedules in pediatric oncology therapy has led simultaneously to an Page 8 of 11Seifert et al. BMC Cancer (2022) 22:652 Table 4 Secondary outcomes chemotherapy‑associated toxicity parameter list Secondary outcome parameter: Neutrophil granulocytes Neutropenia, number of days Red blood cell transfusion Transfusion of thrombocyte concentrates Fever, maximum temperature Antibiotics Antimycotics/antifungals Catheter infection Number of C‑reactive protein values/measurements above the norm Number of C‑reactive protein Values threefold above the norm Maximum CRP value Days with fever above 38,5 °C Nausea Emesis Stomatitis Number of days with stomatitis Abdominal pain/cramping Gastritis Obstipation Diarrhea episodes per day Pancreas ultrasonography/sonography Thrombosis Creatinine clearance Steroid diabetes Cushing syndrome Arrhythmia Cardiac function Echocardiography, left ventricular shortening fraction Pain Central neurotoxicity Fatigue Peripheral neurotoxicity Mood swings: depression Mood swings: anxiety Mood swings: euphoria General wellbeing Skin alterations Osteonecrosis Delay in onset of the last treatment block Hemoglobin Thrombocytes Leucocytes maximum value Leucocytes minimum value CRP maximum value Alpha lipase Glucose Aspartat amino transferase (AST, ASAT) Page 9 of 11Seifert et al. BMC Cancer (2022) 22:652 increase of survival and targeted therapeutics with better outcomes and resulting in less toxicity [21, 22]. One pos- sible explanation for a lack in demonstrable gains in toxic- ity measures is the ceiling effect of targeted treatments and optimized symptom management. However, studies that systematically research the effects of combined and comprehensive AST have been markedly absent. This study contributes significantly to this data gap whereby integrative treatments such as AST are in demand [7] especially in pediatric oncology. AST and other integrative treatments are often already being given by parents of children suffering from chronic con- ditions such as cancer in Germany as a possible means of assisting their child through difficult circumstances without specific effects being monitored within clinical trials [2, 13]. A singular known case report has previously raised the possibility of a connection between the promo- tion of tumor progression of a non-Hodgkin lymphoma at the subcutaneous injection site of viscum album ther- apy [23]. However, this study makes a strong case, along with other published findings, to demonstrate the safety of mistletoe injections in pediatric oncology [24, 25]. Where other areas of integrative medicine have shown efficacious results [26], facilitating a study design that investigates efficacy of combined AMP has provided an important lesson for the design of future research. Logis- tical and financial trade-offs must be carefully weighed and caution is needed in expediating hopeful outcomes for pediatric oncology patients, even if potential benefits to the quality of life may exist. While rigorous research is still needed for the application of comprehensive AST, a targeted approach, focusing for instance on one malig- nancy population or with a mixed-method design would potentially better capture effects of AMP. Conclusions This study investigated an anthroposophic supportive therapy concept consisting of 19 medications as add-on therapy to standard treatment in children with cancer. For both the primary target criterion toxicity sum score and secondary target parameters, no advantage of using anthroposophic supportive therapy could be shown in this setting. Considering the previous clinical experi- ence in the study population, it can be assumed that the anthroposophic supportive therapy can be applied safely. A key result is that there was no delay in therapy or reduction in therapy in the intervention group nor a statistical difference in 5-year survival as a result of the use of anthroposophic supportive therapy; an essential precondition for effective application of chemotherapy. Notable methodological and logistical lessons were dem- onstrated about the application of a supportive therapy concept in pediatric oncology that has important trans- ferability for future research. Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12885‑ 022‑ 09703‑0. Additional file 1. Acknowledgements The authors would like to recognize the contributions of the late Uta Bierbach from the Department of Pediatrics, Jena University Hospital, Jena, Germany, for her contribution to the study. Authors’ contributions GS: conceptualization, methodology, investigation, resources, data curation, writing – original draft preparation, writing – review and editing, supervision, project administration, funding acquisition. SBB: writing – original draft prepa‑ ration, formal analysis, writing ‑ review and editing, visualization. GC: meth‑ odology, investigation, data curation, writing – review and editing, project administration. FIK: validation, formal analysis, writing – original draft prepara‑ tion, writing – review and editing, visualization. AB: investigation, resources, data curation, writing – review and editing. TB: investigation, resources, data curation, writing – review and editing. CFC: investigation, resources, data curation, writing – review and editing. SC: investigation, resources, data cura‑ tion, writing – review and editing. JF: investigation, resources, data curation, writing – review and editing. SG: investigation, resources, data curation, writing – review and editing. BG: investigation, resources, data curation, writ‑ ing – review and editing. CvH‑H. HNL: investigation, resources, data curation, writing – review and editing. DM: investigation, resources, data curation, writ‑ ing – review and editing. MN: investigation, resources, data curation, writing – review and editing. FN: investigation, resources, data curation, writing – review and editing. AP: investigation, resources, data curation, writing – review and Table 4 (continued) Secondary outcome parameter: Alanin amino transferase (ALT, ALAT) Bilirubin Creatinine Amylase Fibrinogen Antithrombin III (AT‑III) Proteinuria prothrombin time (PTT) https://doi.org/10.1186/s12885-022-09703-0 https://doi.org/10.1186/s12885-022-09703-0 Page 10 of 11Seifert et al. BMC Cancer (2022) 22:652 editing. BW: investigation, resources, data curation, writing – review and edit‑ ing. TZ: investigation, resources, data curation, writing – review and editing. GH: resources, data curation, writing – review and editing, supervision, project administration, funding acquisition. AL: resources, data curation, writing – review and editing, supervision, project administration, funding acquisition. The author(s) read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Main sponsor‑ ship was provided by: Helixor Heilmittel GmbH & Co. KG, Rosenfeld. Additional finacial support was provided by: WALA Heilmittel GmbH, Bad Boll/Eckwälden; Weleda AG, Schwäbisch Gmünd: Mahle Stiftung, Stuttgart; Software AG Stif‑ tung, Darmstadt; Stiftung Helixor, Rosenfeld; and Injex Pharma AG, Berlin. Availability of data and materials Datasets generated and/or analyzed during the current study or full study protocol are available upon request via the corresponding author. Declarations Ethics approval and consent to participate The authors declare no competing interests. The trial was approved by the Institutional Review Board of Charité ‑ Universitätsmedizin Berlin as the responsible ethics committee (EA2/141/05). Prior to the trial commencement, the study was registered at the European Union (EU) Drug Clinical Trials Reg‑ ister (EudraCT‑ No: 2004–002711‑83). Furthermore, all participants provided written informed consent in accordance to the Declaration of Helsinki. Consent for publication This manuscript contains no individual data needing additional consent and is therefore not applicable. Competing interests None of the authors have competing interests to declare. Author details 1 Department of Pediatrics, Division of Oncology and Hematology, Charité ‑ Universitätsmedizin Berlin, Berlin, Germany. 2 Department of Pediatric Hema‑ tology and Oncology, University Children’s Hospital, Düsseldorf, Germany. 3 Department of Pediatric Hematology and Oncology, University Hospital Bonn, University of Bonn, Bonn, Germany. 4 Institute of Applied Analysis and Numerical Simulation, Research Group for Computational Methods for Uncertainty Quantification, University of Stuttgart, Stuttgart, Germany. 5 Department of Pediatrics, Martin Luther University Halle‑Wittenberg, Halle, Germany. 6 Division of Pediatric Oncology, Hematology and Palliative Medicine Section, Department of Pediatrics and Adolescent Medicine, University Medicine Rostock, Rostock, Germany. 7 Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Regensburg, Regensburg, Germany. 8 Center for Palliative Care and Pediatric Pain Medicine, Saarland University Medical Center, Homburg, Germany. 9 Department of Pediatrics, Jena University Hospital, Jena, Germany. 10 Department of Pedi‑ atric Hematology and Oncology, University Medicine, Greifswald, Germany. 11 Department of Hematology Oncology, University Children’s Hospital, Tübingen, Germany. 12 Department of Human Medicine, Faculty of Health, University Witten/Herdecke, Herdecke, Germany. 13 Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany. 14 Pediatric Oncology Center, Department of Pediatrics, Technische Universität München, Munich, Germany. 15 Department of Pediatric Cardiology, Pulmonology and Pediatric Intensive Care Medicine, University Children’s Hospital, Tübingen, Germany. 16 Depart‑ ment of Pediatric Hematology and Oncology, Hospital Bremen‑Mitte, Bremen, Germany. 17 Department of Pediatric Hematology‑Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany. 18 Department of Integrative Pediatric and Adolescent Medicine, Gemeinschaftskrankenhaus Herdecke, Herdecke, Germany. 19 Centre for Integrative Medicine, University of Witten/ Herdecke, Witten, Germany. Received: 26 January 2022 Accepted: 24 May 2022 References 1. Ernst E. The current position of complementary/alternative medicine in cancer. Eur J Cancer. 2001;39(16):2273–7. 2. Längler A, Spix C, Seifert G, Gottschling S, Graf N, Kaatsch P. Comple‑ mentary and alternative treatment methods in children with cancer: a population‑based retrospective survey on the prevalence of use in Germany. Eur J Cancer. 2008;44(15):2233–40. 3. Längler A, Spix C, Edelhäuser F, Martin DD, Kameda G, Kaatsch P, et al. Anthroposophic medicine in paediatric oncology in Germany: results of a population‑based retrospective parental survey. Pediatr Blood Cancer. 2010;55(6):1111–7. 4. Kienle GS, Albonico HU, Baars E, Hamre HJ, Zimmermann P, Kiene H. Anthroposophic medicine: an integrative medical system originating in europe. Glob Adv Health Med. 2013;2(6):20–31. 5. Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008;2008(2):Cd003297. 6. Steuer‑Vogt MK, Bonkowsky V, Ambrosch P, Scholz M, Neiβ A, Strutz J, et al. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer. 2001;37(1):23–31. 7. Stritter W, Rutert B, Eidenschink C, Eggert A, Längler A, Holmberg C, et al. Perception of integrative care in paediatric oncology‑perspectives of parents and patients. Complement Ther Med. 2020;56:102624. 8. Zuzak TJ, Wasmuth A, Bernitzki S, Schwermer M, Längler A. Safety of high‑ dose intravenous mistletoe therapy in pediatric cancer patients: a case series. Complement Ther Med. 2018;40:198–202. 9. Seifert G, Rutkowski S, Jesse P, Madeleyn R, Reif M, Henze G, et al. Anthroposophic supportive treatment in children with medulloblastoma receiving first‑line therapy. J Pediatr Hematol Oncol. 2011;33(3):e105–8. 10. Seifert G, Tautz C, Seeger K, Henze G, Laengler A. Therapeutic use of mis‑ tletoe for CD30+ cutaneous lymphoproliferative disorder/lymphomatoid papulosis. J Eur Acad Dermatol Venereol. 2007;21(4):558–60. 11. Kaestner J, Schlodder D, Preussler C, Gruhn B. Supportive mistletoe therapy in a patient with metastasised neuroblastoma. BMJ Case Rep. 2019;12(3):e227652. 12. Kameda G, Kempf W, Oschlies I, Michael K, Seifert G, Längler A. Nodal ana‑ plastic large‑cell lymphoma ALK‑1‑ with CD30+ cutaneous lymphopro‑ liferation treated with mistletoe: spontaneous remission or treatment response? Klin Padiatr. 2011;223(6):364–7. 13. Gottschling S, Gronwald B, Schmitt S, Schmitt C, Längler A, Leidig E, et al. Use of complementary and alternative medicine in healthy children and children with chronic medical conditions in Germany. Complement Ther Med. 2013;21(Suppl 1):S61–9. 14. EudraCT (European Union Drug Regulating Authorities Clinical Trials Database). Anthroposophic Supportive Therapy Trial Regis‑ tration. EU Clinical Trials Register 2004. Report No.: Project‑Code: 09–2004‑PaedonkoChar. 15. Association WM. World medical Association declaration of Helsinki. Ethi‑ cal principles for medical research involving human subjects. Bull World Health Organ. 2001;79(4):373. 16. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, et al. Long‑term results of four consecutive trials in childhood ALL per‑ formed by the ALL‑BFM study group from 1981 to 1995. Berlin‑Frankfurt‑ Münster Leukemia. 2000;14(12):2205–22. 17. Sencer SF, Zhou T, Freedman LS, Ives JA, Chen Z, Wall D, et al. Traumeel S in preventing and treating mucositis in young patients undergoing SCT: a report of the Children’s oncology group. Bone Marrow Transplant. 2012;47(11):1409–14. 18. Tröger W, Galun D, Reif M, Schumann A, Stanković N, Milićević 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(18):3788–97. 19. Augustin M, Bock PR, Hanisch J, Karasmann M, Schneider B. Safety and efficacy of the long‑term adjuvant treatment of primary intermedi‑ ate‑ to high‑risk malignant melanoma (UICC/AJCC stage II and III) with a standardized fermented European mistletoe (Viscum album L.) extract. Results from a multicenter, comparative, epidemiological cohort study in Germany and Switzerland. Arzneimittelforschung. 2005;55(1):38–49. 20. Piao BK, Wang YX, Xie GR, Mansmann U, Matthes H, Beuth J, et al. Impact of complementary mistletoe extract treatment on quality of life in breast, Page 11 of 11Seifert et al. BMC Cancer (2022) 22:652 • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • At BMC, research is always in progress. Learn more biomedcentral.com/submissions Ready to submit your researchReady to submit your research ? Choose BMC and benefit from: ? Choose BMC and benefit from: ovarian and non‑small cell lung cancer patients. A prospective rand‑ omized controlled clinical trial. Anticancer Res. 2004;24(1):303–9. 21. Simone JV, Lyons J. The evolution of cancer care for children and adults. J Clin Oncol. 1998;16(9):2904–5. 22. Adamson PC. Improving the outcome for children with cancer: develop‑ ment of targeted new agents. CA Cancer J Clin. 2015;65(3):212–20. 23. Hagenah W, Dörges I, Gafumbegete E, Wagner T. Subcutaneous manifes‑ tations of a centrocytic non‑Hodgkin lymphoma at the injection site of a mistletoe preparation. Dtsch Med Wochenschr. 1998;123(34–35):1001–4. 24. Stumpf C, Rosenberger A, Rieger S, Tröger W, Schietzel M. Mistletoe extracts in the therapy of malignant, hematological and lymphatic diseases‑‑a monocentric, retrospective analysis over 16 years. Forsch Komplementarmed Klass Naturheilkd. 2000;7(3):139–46. 25. Kuehn JJ. Favorable long‑term outcome with mistletoe therapy in a patient with centroblastic‑centrocytic non‑Hodgkin lymphoma. Dtsch Med Wochenschr. 1999;124(47):1414–8. 26. Mühlenpfordt I, Stritter W, Bertram M, Ben‑Arye E, Seifert G. The power of touch: external applications from whole medical systems in the care of cancer patients (literature review). Support Care Cancer. 2020;28(2):461–71. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Integrative medicine during the intensive phase of chemotherapy in pediatric oncology in Germany: a randomized controlled trial with 5-year follow up Abstract Background: Methods: Results: Discussion: Introduction Background Objective and hypothesis including 5-year follow up data Methods Trial design Study recruitment Study intervention Study randomization Results Sample description Primary outcome: the toxicity sum score (TSS) Secondary outcome: determination of chemotherapy-associated toxicity Adverse events Serious adverse events Outcome of five-year follow up on event-free and overall survival & safety Discussion Limitations Conclusions Acknowledgements References