DÄ internationalArchive39/2021Complementary Medicine in the Treatment of Cancer Patients

Clinical Practice Guideline

Complementary Medicine in the Treatment of Cancer Patients

Dtsch Arztebl Int 2021; 118: 654-9. DOI: 10.3238/arztebl.m2021.0277

Hübner, J; Beckmann, M; Follmann, M; Nothacker, M; Prott, F J; Wörmann, B

Background: Approximately half of all patients with cancer use at least one method of complementary medicine during or after tumor treatment. The substances most commonly taken are micronutrients, food supplements, and plant extracts.

Methods: This guideline is based on pertinent articles retrieved by a systematic search in the Medline, Cochrane Library, Embase, PsycInfo, and Cinahl databases.

Results: The evidence is offen scant for any effect of a complementary method on patient-relevant endpoints such as relief of disease symptoms, reduction of treatment side effects, or prolonged survival. Micronutrients are available in different compositions, and their dosages vary. In most studies on the use of vitamins and trace elements by cancer patients, the blood level of the substance in question was not measured before its administration, so that it remains unknown whether a deficiency was present. For this reason, no well-founded conclusion on the effects of these substances can be drawn, and their use cannot be recommended in most cases. On the other hand, there is high-level evidence supporting physical exercise by cancer patients during and after their treatment. For patients with any type of cancer, mortality is lower among those who perform more physical exercise, whether before or after they receive the diagnosis of cancer (exercise before diagnosis, hazard ratio [HR] 0.82, 95% confidence interval [CI] [0.79; 0.86]; exercise after diagnosis, HR 0.63, 95% CI [0.53; 0.75]). Physical exercise during and after treatment for cancer should, therefore, be recommended to all cancer patients.

Conclusion: The inherent positive attribute of complementary medicine is patient empowerment: it enables patients to help themselves in an active way even while undergoing cancer treatment, as well as afterward. To avoid risks to health, patients should be instructed about unsafe methods, asked repeatedly about their use of complementary medicine, and informed specifically about potential interactions between such interventions and their cancer treatment.

LNSLNS

The terms “complementary medicine“ and “alternative medicine“ are often used interchangeably in everyday practice and summarized under the term “complementary and alternative medicine“ (CAM). The two terms are to be distinguished in the context in which they are applied: Alternative medicine sees itself as an alternative to conventional treatment. By contrast, complementary methods are used in conjunction with conventional treatment and differ from alternative methods in that they see themselves as a supplement to conventional treatment strategies.

It is often almost impossible to draw clear distinctions as to which methods fall under alternative medicine and which under complementary medicine, since the majority of techniques and methods are used in both contexts.

Complementary medicine attracts a high level of interest from cancer patients. About every second cancer patient uses one of these methods. A common motivating factor is the desire to take personal action. These efforts should be supported—taking into account a positive risk-benefit ratio. With regard to treatment modalities requiring the administration of a substance to the patient, the question of drug interactions is very important. For the other modalities, protecting patients from methods without proof of effectiveness, for which they invest time and/or money, is also a concern. In addition, it is well established that patients who, due to placebo effects, have made positive experiences with per se ineffective methods, initially tend to seek treatment with such methods even if they are diagnosed with a serious cancer (e1, e2, e3, e4), thus letting valuable time for effective treatment pass.

This guideline is concerned with complementary interventions which can be used in addition to organ-specific guideline-adherent therapy.

Methods

The Guidance Manual and Rules for Guideline Development of the Association of the Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) for S3-level clinical practice guidelines was used as a template for the methodological approach (1). In the creation of this S3-level clinical practice guideline, a representative group of 46 medical societies and institutions, including patient representatives, was involved, coordinated by the leading medical societies German Cancer Society (DKG, Deutsche Krebsgesellschaft), German Society of Gynecology and Obstetrics (DGGG, Deutsche Gesellschaft für Gynäkologie und Geburtshilfe), German Society of Hematology and Medical Oncology (DGHO, Deutsche Gesellschaft für Hämatologie und medizinische Onkologie), and German Society of Radiation Oncology (DEGRO, Deutsche Gesellschaft für Radioonkologie). Methodological support was provided by the Office of the Oncology Guideline Program and the AWMF Institute for Medical Knowledge Management. The Medline, Cochrane Library Embase, PsycInfo, and Cinahl databases were searched for systematic reviews and primary studies to answer the key questions. Literature screening was completed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria.

From the hits, 445 pertinent studies were selected (Figure). The critical review of the studies selected for their strength of evidence was carried out according to the 2009 Levels of Evidence 1 document of the Oxford Centre for Evidence-Based Medicine (e5). Relevant data were extracted in evidence tables. On this basis, recommendations were agreed upon and background texts were prepared.

Search flowchart of the S3-level clinical practice guideline “Complementary Medicine Treatment of Cancer Patients“; CAM, complementary and alternative medicine
Figure
Search flowchart of the S3-level clinical practice guideline “Complementary Medicine Treatment of Cancer Patients“; CAM, complementary and alternative medicine

In the following, we will present the key recommendations on:

  • Biologically based therapies (i.e. micronutrients, herbal medicines [phytotherapeutics] and other substances which are introduced into the body)
  • Body-based therapies.

The Table provides an overview of all complementary medicine methods and indications included in this guideline.

Complementary methods and recommendations with grades of recommendation “should”/ “ought to” by treatment goals
Table
Complementary methods and recommendations with grades of recommendation “should”/ “ought to” by treatment goals

Results

All in all, the newly created guideline (2) includes 94 recommendations, 83 of which are evidence-based. The remaining recommendations are based on expert consensus (EC). In addition, a questionnaire was developed which is regularly handed out to patients while they are undergoing cancer treatment. It is intended to identify the need for advice and inform patients about potential interactions (ePatient Questionnaire).

Micronutrients

The majority of studies on the use of vitamins and trace elements in oncology are flawed by the fact that typically no baseline levels are reported and substitution was not limited to patients with deficiency. No standard values are available for secondary plant compounds—what is known is that their bioavailability is usually low.

Selenium

A distinction must be made between organic (selenium yeast/selenomethionine) and inorganic selenium compounds (such as sodium selenite). The intake of organic forms can soon lead to overdosing..

Two randomized studies showed a protective effect of sodium selenite against radiation therapy-related adverse events affecting mucosal tissues of the head/neck and pelvic regions in selenium-deficient patients with advanced head/neck cancer and cervical/uterine cancer, respectively. The study by Büntzel et al. 2010 (3) showed a reduced mean for dysphagia at the seventh week of irradiation (1,533 versus 2.167; p = 0.05). In the study by Mücke et al. 2013 (4), the incidence of at least grade 2 diarrhea was 20.5% and 44.5% in the selenium arm and control arm, respectively (p = 0.04).

Protective administration of sodium selenite may be considered in these patients.

Vitamin C

Vitamin C is given as so-called high-dose vitamin C in doses of grams to prevent side effects of cancer treatment or to act directly on tumor growth. However, data of a meta-analysis do not support such an effect (5). At the same time, there is evidence to suggest that oral intake of vitamin C reduces the effect of chemotherapy and radiation therapy (e6). For this reason, the guideline makes a “should not“ recommendation with regard to oral administration of vitamin C in higher doses in cancer patients. For high-dose intravenous vitamin C, the available evidence is inconclusive.

Vitamin D

In cancer patients, the role of vitamin D is not limited to reducing the risk of osteoporosis. 25-OH vitamin D levels should be measured to detect vitamin D deficiency.

According to the Robert Koch Institute, 15% of the adult population suffer from inadequate vitamin D supply, with 25-OH vitamin D serum levels below 30 nmol/L (below 12 ng/mL), and further 41% have suboptimal serum levels between 30 and 50 nmol/L (12 and 20 ng/mL) (6).

The effectiveness of vitamin D with regard to overall survival and progression-free survival was evaluated in three randomized controlled trials RCTs) on patients with prostate cancer (7, 8, 9) and in a small randomized study on patients with head and neck cancer (10). Because of methodological shortcomings, the strength of evidence of all of these studies was inadequate.

Three further randomized controlled trials primarily evaluated aromatase inhibitor-induced musculoskeletal symptoms in breast cancer patients (11, 12, 13). Here, the data are contradictory; thus, the guideline does not make a recommendation for or against vitamin D administration in these patients, other than compensating for vitamin D deficiency.

Vitamin E

Similar to vitamin C, the evidence in support of potential damage along with the lack of proven benefits was combined into a negative recommendation: Vitamin E ought not to be given to influence overall survival or progression-free survival (14, 15) or to prevent and treat chemotherapy-induced polyneuropathy (16) or oral mucositis (15, 17, 18).

Herbal medicines/phytotherapeutics

Besides micronutrients, phytotherapeutics represent the second major group of biologically based substances used by cancer patients. In Germany, some phytotherapeutics are on the market as medicines, some as dietary supplements. Therefore, differences in the quality of manufacturing processes and products are to be taken into account. Significantly underdosed or homeopathic products, containing the active ingredient in non-effective concentrations or not at all, are also common to find.

Ginger

With regard to ginger, two older systematic reviews with in total eight RCTs and nine more recent RCTs were assessed for the effect of ginger on chemotherapy-induced nausea and vomiting (CINV). Most of these studies are methodologically flawed. Taking all findings, especially those of the better designed studies (19, 20), into account, it was stated in the guideline that ginger may be considered in addition to guideline-adherent antiemetic regimens in the treatment of chemotherapy‐induced nausea and vomiting in these patients. In a subgroup of patients, the majority of whom received low or moderate emetogenic chemotherapy, nausea was more severe and lasted longer in patients who took higher doses of ginger or both ginger and aprepitant (e7). Based on level 2b evidence, the use of ginger may be considered in addition to guideline-adherent antiemetic regimens in the treatment of chemotherapy‐induced nausea and vomiting in these patients.

Mistletoe

Three reviews/meta-analyses and individual RCTs on the efficacy of whole plant mistletoe extract (Viscum album L.) in improving overall survival in patients with various cancers yielded inconsistent results. While some showed positive results, others failed to demonstrate statistically significant efficacy (21, 22, 23). The systematic review with meta-analysis published in 2020, which included 32 studies, calculated an improvement in survival (hazard ratio [HR]: 0.59; 95% confidence interval [0.53; 0.65], p<0.0001) (22); however, an earlier high-quality Cochrane review already concluded that the heterogeneity and insufficient quality of the data meant that a meta-analysis was not useful (23). For example, the quality of reporting and conduction of some of the included studies was very limited and the definitions of survival and the methods used to measure it varied widely. There is insufficient data available to allow a definite final assessment. Therefore, the guideline does not make a recommendation for or against the prescription of products with whole mistletoe extract (Viscum album L.) with the goal to improve survival.

There are inconsistent data from systematic reviews/meta-analyses and RCTs in which medicinal products containing whole plant mistletoe extract (Viscum album L.) were subcutaneously administered to patients with solid tumors to improve quality of life (23, 24). Here, the mandate holders voted in favor of a “may be considered” recommendation: The subcutaneous administration of whole plant mistletoe extract (Viscum album L.) may be considered for therapeutic use in patients with solid tumors with the goal to improve patient quality of life.

St. John’s wort

St. John’s wort products are not inferior to conventional drugs in the treatment of mild to moderate depression. However, no studies are available which have evaluated the efficacy of St. John’s wort for depression in cancer patients. Patients taking St. John’s wort on their own initiative should be advised of the risk of serious interactions with other medications.

Ketogenic diets

Cancer diets have been popular among cancer patients for years and are used sometimes to directly fight the cancer (“starve the cancer cells“) and sometimes to improve cancer treatment tolerability.

The available evidence includes one systematic review based on case series and case reports (25) and data from three RCTs (26, 27, 28). In all studies, this approach resulted in weight loss, corresponding to malnutrition according to the screening criteria for assessing nutritional status. As a rule, ketogenic nutrition should not be recommended in normal weight and underweight patients. No studies were found that showed improvements in survival as the result of ketogenic diets.

Yoga

Yoga comprises guidance on ethical behavior and physical exercise as well as breathing, concentration and meditation techniques. In Germany, very different styles of yoga are offered. Data on the effect of yoga on quality of life and distressing symptoms are available. When evaluating these data, it is important to keep in mind that many studies did not describe in detail what the intervention consisted of and what the proportions of physical exercises, breathing techniques and meditation techniques were.  

The results for improvements in global and cancer-specific quality of life are inconsistent (29). Thus, a “may be considered” recommendation was made by the mandate holders: Yoga may be considered in these patients to improve global and cancer-specific quality of life. With regard to reduction of fatigue, the results are consistent: Yoga should be recommended to reduce fatigue in these patients (29, 30). Further “may be considered” recommendations were made for the use of yoga for disorders of initiating and maintaining sleep (29), cognitive impairment and menopausal symptoms in patients with breast cancer (31, e8).

Physical exercise

During the development of the guideline, a systematic search on sports or physical exercise was conducted for the endpoints fatigue and quality of life during cancer treatment. With regard to mortality, a guideline adaptation was undertaken (32), adding data from a recent meta-analysis of 136 studies. For patients with any type of cancer, mortality was lower among those who performed more physical exercise, whether before or after they received the diagnosis of cancer (exercise before diagnosis: HR:  0.82; [0.79; 0.86]; exercise after diagnosis: HR: 0.63; [0.53; 0.75]) (33). Despite the limitation that these studies were not designed as prospective randomized controlled trials, overall there is good evidence available to support one of the few strong recommendations in this guideline: Physical exercise during and after treatment for cancer should be recommended to all cancer patients. The goal of at least 150 min of moderate or 75 min of strenuous physical exercise per week should be achieved again or attempted to be maintained as early as possible after diagnosis.

A mix of endurance, strength, coordination and flexibility training is recommended for training guidance.

All in all, 27 systematic reviews on the effect of sporting activity during cancer therapy on quality of life and fatigue were identified. The meta-analysis by Oberoi et al. 2018 (34) included a total of 134 randomized controlled trials on various types of cancer and showed a reduction in fatigue (standardized mean difference [SMD]: −0.49; [−0.60; −0.37]); p<0.00001, I² = 85%). Seven studies with prostate cancer patients were included in the meta-analysis (35). A subgroup analysis of three high-quality studies showed a moderate positive effect (SMD: 0.33; [0.08; 0.58]; median follow-up: 12 weeks; I² = 0%).

Physical activity and sports should be recommended with the goal of maintaining quality of life and treating and preventing cancer-specific fatigue.

Discussion

For the development of this guideline, the published studies were rigorously searched and their strength of evidence was assessed. It was found that for most of the methods only few scientific data were available and high-level evidence studies are scarce.

This makes it all the more important to carefully weigh up the benefits and risks when giving advice to patients. While several studies point to benefits with regard to certain side effects of cancer therapy or improvements in quality of life, only few studies systematically evaluated data on potential harm in the form of side effects and drug interaction. The latter should not be underestimated, as several studies reported that in one-third of all patients, on average, interactions with drugs used for cancer treatment are likely to occur during complementary treatment. In addition, such an interaction is at least possible in another one third of patients (e9, e10, e11, e12).

Therefore, it is a key recommendation supported by strong expert consensus that all patients should as early as possible be asked about current or planned use of complementary treatments and be informed specifically about potential interactions between these treatments and cancer treatment. Interactions are not to be expected with complementary methods that are not biologically based. An apparent inconsistency within the guideline is explained by this difference. In the chapters with potentially harmful methods, “ought not to” recommendations were generally made in the absence of evidence of a benefit, while in the other chapters “may be considered” recommendations were frequently made even if no superiority compared to placebo was proven.

Conclusion

Complementary medicine comprises supplementary facultative methods. If well coordinated with the actual cancer treatment, it can be used above all with the goal of improving patient quality of life, promoting patient empowerment and preventing side effects. Thus, methods that can be used by patients independently are particularly useful.

All risks and benefits must be carefully weighed In order to prevent side effects and drug interactions, regular assessments and, at times, patient counseling are required. Here, the patient guideline can help to alleviate the workload of physicians and nurses, especially if their center or practice cannot offer well-founded advice on the topic.

Acknowledgement

We thank all mandate holders and experts who have on a voluntary basis dedicated considerable time and effort to the creation of this guideline: Barbara Baysal, Peggy Becker, Matthias Beckmann, Antje Belau, Tanja Bender, Hartmut Bertz, Thorsten Bruns, Jürgen Brust, Jens Büntzel, Stephanie E. Combs, Holger Cramer, Gustav Dobos, Dirk Domagk, Lothar Eberhardt, Dr. Stefan Fichtner-Feigel, Ulrich Freitag, Stefan Fuxius, Shahram Ghanaati, Katharina Glassen, Bernt Göckel-Beining, Daniela Göppner, Sven Gottschling, Christian Grohé, Carolin Hack, Andrea Hahne, Heidemarie Haller, Annette Hasenburg, Katja Hennig, Ulla Henscher, Michael Höckel, Markus Horneber, Manfred Johannsen, Sabine Jonas, Stefanie Joos,. Christoph Kahl, Katharina Kähler, Sabine Kirton, Petra Klose, Ingeborg Koch, Jost Langhorst, Alfred Längler, Carmen Loquai, Harald Matthes, Oliver Micke, Dorothea Müller, Franz-Josef Prott, Matthias Rostock, Andre-Robert Rotmann, Manuela Schallenburger, Christoph Schäper, Jan Schildmann, Thorsten Schmidt, Heike Schmidt, Dr. Stefanie Seeling, Norbert Senninger, Andreas Sesterhenn, Diana Steinmann, Cornelia Strietzel, Reina Tholen, Claas Ulrich, Regina von Rochow, Steffen Wagner, Walter, Arved Weimann, Joachim Weis, Eva Winkler, Claudia Witt, Achim Wöckel, Bernhard Wörmann, Luzia Valentini.

Funding

The development of the guideline was part of the Oncology Guideline Program of the German Cancer Aid Foundation (reference number 111513).

Conflict of interest statement
The authors declare that they have no conflict of interest.

Manuscript received on 18 May 2021; revised version accepted on 28 July 2021

Translated from the original German by Ralf Thoene, MD.

Clinical practice guidelines are not peer-reviewed in Deutsches Ärzteblatt, as well as in many other journals, because (S3) clinical practice guidelines are texts which have already been repeatedly evaluated, discussed and broadly consented by experts (peers).

Corresponding author
Prof. Dr. med. Jutta Hübner
Klinik für Innere Medizin II
Universitätsklinikum Jena
Am Klinikum 1, 07747 Jena, Germany
jutta.huebner@med.uni-jena.de

Cite this as:
Hübner J, Beckmann M, Follmann M, Nothacker M, Prott FJ,
Wörmann B: Clinical practice guideline: Complementary medicine in the treatment of cancer patients. Dtsch Arztebl Int 2021; 118: 654–9. DOI: 10.3238/arztebl.m2021.0277

Supplementary material
eReferences, ePatient Questionnaire
www.aerzteblatt.de/m2021.0277

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German Cancer Society (DKG): Prof. Dr. med. Jutta Hübner
German Society of Obstetrics and Gynecology (DGGG): Prof. Dr. med. Matthias Beckmann
Oncological Guideline Program (OL): Dr. med. Markus Follmann
Association of the Scientific Medical Societies in Germany (AWMF):
Dr. med. Monika Nothacker
German Society of Radiation Oncology (DEGRO): Prof. Dr. med. Franz Josef Prott
German Society of Hematology and Medical Oncology (DGHO):
Prof. Dr. med. Bernhard Wörmann
Search flowchart of the S3-level clinical practice guideline “Complementary Medicine Treatment of Cancer Patients“; CAM, complementary and alternative medicine
Figure
Search flowchart of the S3-level clinical practice guideline “Complementary Medicine Treatment of Cancer Patients“; CAM, complementary and alternative medicine
Complementary methods and recommendations with grades of recommendation “should”/ “ought to” by treatment goals
Table
Complementary methods and recommendations with grades of recommendation “should”/ “ought to” by treatment goals
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2.Das Portal der wissenschaftlichen Medizin, AWMF: Komplementärmedizin in der Behandlung von onkologischen PatientInnen. 2017. www.leitlinienprogramm-onkologie.de/leitlinien/komplementaermedizin/ (last accessed on 16 July 2021).
3.Büntzel J, Riesenbeck D, Glatzel M, et al.: Limited effects of selenium substitution in the prevention of radiation-associated toxicities. Results of a randomized study in head and neck cancer patients. Anticancer Res 2010; 30: 1829–32.
4.Muecke R, Micke O, Schomburg L, et al.: Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology—a subgroup analysis of a multicenter, phase III trial. Radiat Oncol 2013; 8: 72 CrossRef MEDLINE PubMed Central
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6.Rabenberg M, Scheidt-Nave C, Busch MA, Rieckmann N, Hintzpeter B, Mensink GB: Vitamin D status among adults in Germany—results from the German Health Interview and Examination Survey for Adults (DEGS1). BMC Public Health 2015; 15: 1–15 CrossRef MEDLINE PubMed Central
7.Attia S, Eickhoff J, Wilding G, et al.: Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent prostate cancer. Clin Cancer Res 2008; 14: 2437–43 CrossRef MEDLINE PubMed Central
8.Beer TM, Ryan CW, Venner PM, et al.: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 2007; 25: 669–74 CrossRef MEDLINE
9.Scher HI, Jia X, Chi K, et al.: Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol 2011; 29: 2191–8 CrossRef MEDLINE
10.Walsh JE, Clark A-M, Day TA, Gillespie MB, Young MRI: Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma. Hum Immunol 2010; 71: 659–65 CrossRef MEDLINE PubMed Central
11.Khan QJ, Kimler BF, Reddy PS, et al.: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial. Breast Cancer Res Treat 2017; 166: 491–500 CrossRef MEDLINE
12.Rastelli AL, Taylor ME, Gao F, et al.: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat 2011; 129: 107–16 CrossRef MEDLINE
13.Shapiro AC, Adlis SA, Robien K, et al.: Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). Breast Cancer Res Trea 2016; 155: 501–12 CrossRef MEDLINE PubMed Central
14.Bairati I, Meyer F, Jobin E, et al.: Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer 2006; 119: 2221–4 CrossRef MEDLINE
15.Ferreira PR, Fleck JF, Diehl A, et al.: Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: a double-blind randomized trial. Head Neck 2004; 26: 313–21 CrossRef MEDLINE
16.Kottschade LA, Sloan JA, Mazurczak MA, et al.: The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Care Cancer 2011; 19: 1769–77 CrossRef CrossRef MEDLINE
17.Azizi A, Alirezaei S, Pedram P, Mafi AR: Efficacy of topical and systemic vitamin E in preventing chemotherapy-induced oral mucositis. Rep Pract Oncol Radiother 2015; 2: e796 CrossRef
18.Ghoreishi Z, Shidfar F, Iravani M, Esfahani A, Ghavamzadeh A: Effect of vitamin E on chemotherapy-induced mucositis and neutropenia in leukemic patients undergoing bone marrow transplantation. Asia Pac J Clin Oncol 2007; 3: 113–8 CrossRef
19.Marx W, McCarthy AL, Ried K, et al.: The effect of a standardized ginger extract on chemotherapy-induced nausea-related quality of life in patients undergoing moderately or highly emetogenic chemotherapy: a double blind, randomized, placebo controlled trial. Nutrients 2017; 9: 867 CrossRef MEDLINE PubMed Central
20.Konmun J, Danwilai K, Ngamphaiboon N, Sripanidkulchai B, Sookprasert A, Subongkot S: A phase II randomized double-blind placebo-controlled study of 6-gingerol as an anti-emetic in solid tumor patients receiving moderately to highly emetogenic chemotherapy. Med Oncol 2017; 34: 69 CrossRef MEDLINE
21.Freuding M, Keinki C, Micke O, Buentzel J, Huebner J: Mistletoe in oncological treatment: a systematic review : part 1: survival and safety. J Cancer Res Clin Oncol 2019; 145: 695–707 CrossRef MEDLINE
22.Ostermann T, Appelbaum S, Poier D, Boehm K, Raak C, Bussing A: A systematic review and meta-analysis on the survival of cancer patients treated with a fermented Viscum album L. extract (Iscador): an update of findings. Complement Med Res 2020 ; 27: 260–71 CrossRef MEDLINE
23.Horneber MA, Bueschel G, Huber R, Linde K, Rostock M: Mistletoe therapy in oncology. Cochrane Database Syst Rev 2008; 2008: Cd003297 CrossRef
24.Freuding M, Keinki C, Kutschan S, Micke O, Buentzel J, Huebner J: Mistletoe in oncological treatment: a systematic review : Part 2: quality of life and toxicity of cancer treatment. J Cancer Res Clin Oncol 2019; 145: 927–39 CrossRef MEDLINE
25.Erickson N, Boscheri A, Linke B, Huebner J: Systematic review: isocaloric ketogenic dietary regimes for cancer patients. Med Oncol 2017; 34: 72 CrossRef MEDLINE
26.Cohen CW, Fontaine KR, Arend RC, Soleymani T, Gower BA: Favorable effects of a ketogenic diet on physical function, perceived energy, and food cravings in women with ovarian or endometrial cancer: a randomized, controlled trial. Nutrients 2018; 10: 1187 CrossRef MEDLINE PubMed Central
27.Khodabakhshi A, Akbari ME, Mirzaei HR, Mehrad-Majd H, Kalamian M, Davoodi SH: Feasibility, safety, and beneficial effects of MCT-based ketogenic diet for breast cancer treatment: a randomized controlled trial Study. Nutr Cancer 2019; 72: 627–34 CrossRef MEDLINE
28.Freedland SJ, Allen J, Jarman A, et al.: A randomized controlled trial of a 6-month low carbohydrate intervention on disease progression in men with recurrent prostate cancer: Carbohydrate and Prostate Study 2 (CAPS2). Clin Cancer Res 2020; 26: 3035–43 CrossRef MEDLINE
29.Cramer H, Lauche R, Klose P, Lange S, Langhorst J, Dobos G: Yoga for improving health-related quality of life, mental health and cancer-related symptoms in women diagnosed with breast cancer. Cochrane Database Syst Rev 2017; 1: Cd010802 CrossRef MEDLINE PubMed Central
30.Hilfiker R, Meichtry A, Eicher M, et al.: Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med 2018; 52: 651–8 CrossRef MEDLINE PubMed Central
31.Carson JW, Carson KM, Porter LS, Keefe FJ, Seewaldt VL: Yoga of Awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer 2009; 17: 1301–9 CrossRef MEDLINE
32.KCE: Supportive treatment for cancer, part 1: exercise treatment. 2019. www.kce.fgov.be/sites/default/files/atoms/files/KCE_185C_supportive_treatment_cancer_0.pdf (last accessed on 16 July 2021).
33.Friedenreich CM, Stone CR, Cheung WY, Hayes SC: Physical activity and mortality in cancer survivors: a systematic review and meta-analysis. JNCI Cancer Spectr 2020; 4: pkz080 CrossRef MEDLINE PubMed Central
34.Oberoi S, Robinson PD, Cataudella D, et al.: Physical activity reduces fatigue in patients with cancer and hematopoietic stem cell transplant recipients: a systematic review and meta-analysis of randomized trials. Crit Rev Oncol Hematol 2018; 122: 52–9 CrossRef MEDLINE
35.Bourke L, Smith D, Steed L, et al.: Exercise for men with prostate cancer: a systematic review and meta-analysis. Eur Urol 2016; 69: 693–703 CrossRef MEDLINE
e1.Huebner J, Micke O, Muecke R, et al.: User rate of complementary and alternative medicine (CAM) of patients visiting a counseling facility for CAM of a German comprehensive cancer center. Anticancer Res 2014; 34: 943–8.
e2.Paul M, Davey B, Senf B, et al.: Patients with advanced cancer and their usage of complementary and alternative medicine. J Cancer Res Clin Oncol 2013; 139: 1515–22 CrossRef MEDLINE
e3.Huebner J, Prott FJ, Micke O, et al.: Online survey of cancer patients on complementary and alternative medicine. Oncol Res Treat 2014; 37: 304–8 CrossRef MEDLINE
e4.Loquai C, Dechent D, Garzarolli M, et al.: Use of complementary and alternative medicine: a multicenter cross-sectional study in 1089 melanoma patients. Eur J Cancer 2017; 71: 70–9 CrossRef MEDLINE
e5.Centre for Evidence-Based Medicine (CEBM): Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). 2009. www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009 (last accessed on 18 June 2021).
e6.Jung AY, Cai X, Thoene K, et al.: Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am J Clin Nutr 2019; 109: 69–78 CrossRef MEDLINE
e7.Zick SM, Ruffin MT, Lee J, et al.: Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care Cancer 2009; 17: 563–72 CrossRef MEDLINE PubMed Central
e8.Cramer H, Rabsilber S, Lauche R, Kümmel S, Dobos G: Yoga and meditation for menopausal symptoms in breast cancer survivors—a randomized controlled trial. Cancer 2015; 121: 2175–84 CrossRef MEDLINE
e9.Zeller T, Muenstedt K, Stoll C, et al.: Potential interactions of complementary and alternative medicine with cancer therapy in outpatients with gynecological cancer in a comprehensive cancer center. J Cancer Res Clin Oncol 2013; 139: 357–65 CrossRef MEDLINE
e10.Firkins R, Eisfeld H, Keinki C, et al.: The use of complementary and alternative medicine by patients in routine care and the risk of interactions. J Cancer Res Clin Oncol 2018; 144: 551–7 CrossRef MEDLINE
e11.Loquai C, Dechent D, Garzarolli M, et al.: Use of complementary and alternative medicine: a multicenter cross-sectional study in 1089 melanoma patients. Eur J Cancer 2017; 71: 70–9 CrossRef MEDLINE
e12.Loquai C, Dechent D, Garzarolli M, et al.: Risk of interactions between complementary and alternative medicine and medication for comorbidities in patients with melanoma. Med Oncol 2016; 33: 52 CrossRef MEDLINE