Validation of the Questionnaire for the Structured Assessment of the Use of Complementary Medicine Methods and Procedures in Patients from the S3 Guideline Complementary Medicine in Oncology and Practical Use of it in Patients with Gynecological Cancer.

The study protocol was approved by the Ethics Committee of the Friedrich Alexander University Erlangen/Nuremberg on December 30, 2021 with reference code “UFK-IMed_2021”. Written informed consent was provided by all participants. The present study is a cross-sectional study conducted in the Women’s Hospital of the University Hospital Erlangen. The questionnaire for structured assessment of the use of complementary medicine as outlined in the S3 guideline “Complementary Medicine in Oncology” requests age and gender of the subject in the initial line. The subsequent inquiry pertains to the specific interventions used. It is noteworthy that multiple indications of substances or processes are permissible. A comprehensive array of methods and substances are listed, and a cross must be placed in the relevant line if the specified method or substance is being utilized by the patient at present. The final column delineates the symbol indicating potential for interaction, with detailed information provided in the legend. The questionnaire’s legend provides a classification system using three symbols inspired by the traffic light system: a green circle, a yellow rectangle and a red triangle. The green circle indicates that to date there are no known interactions with cancer treatments. The yellow and red symbols indicate a risk of interaction with cancer treatments and requests patients to consult a doctor beforehand. The red triangle is used to identify interventions for which there is clear evidence of an increased risk for utilization, while the yellow color symbolizes a potential risk with largely insufficient data. The questionnaire is supplemented by a brief introduction as well as items that query age and gender and the possibility of comments. Finally, the patient is asked whether they would like a consultation or have any questions about the interventions listed. The complete questionnaire can be found in the appendix Fig. S1 . The present study is concerned with the clinical validation of the questionnaire from the S3 guideline, which has not been employed in this form in the literature so far. A real patient population should demonstrate whether the understanding of the questionnaire is sufficient. As a practical implementation of the questionnaire, a cohort of patients diagnosed with gynecological cancer at the University Hospital Erlangen was selected. The second analysis evaluates this S3 Guideline questionnaire and the use of complementary and integrative medicine (CIM) in this specific field of high interest in oncology today and with high demand for improvement with regard to side effects of therapy and disease status 17 18 . From January 2022 to February 2022 patients from several outpatient departments at the Women’s Hospital Erlangen with different benign and malign diseases were invited to complete the questionnaire for structured assessment of the use of complementary medicine from the S3 guideline “Complementary Medicine in Oncology”, In addition to this, a validation questionnaire was administered to evaluate the comprehensibility of the questions, the time required to complete them, and any issues encountered during the process. The validation questionnaire also solicited suggestions for improvements to the questionnaire design. In half of the patients presented with cancer, but consultations with patients with benign disease were also deliberately chosen as a comparison cohort. Socioeconomic data was incorporated into the study to ensure no bias was introduced. In this study only the level of education and the current employment situation were recorded. Subsequently, after successful validation in the second part of the study, patients with gynecological cancer (endometrial carcinoma, ovarian carcinoma, cervical carcinoma or vulvar carcinoma) were included. The data of women with genital cancer treated in the Women’s Hospital of the University Hospital Erlangen between March and October 2022 were analyzed. The patient population was characterized by descriptive analyses of age, education level, lifestyle factors including dietary habits and physical activity, as well as tumor characteristics and present or past anticancer treatment. In addition, the frequencies of complaints and the use of complementary medicine interventions, classified according to the risk of interactions, were analyzed. The data collected using both questionnaires was supplemented by information on tumor disease from the respective patient file and recorded in a database. Ambiguous and missing information as well as the answer “no information” were listed as missing values and were excluded from the analyses. Multiple answers were possible. Statistical analysis was performed using SPSS Statistics for Windows version 28 (IBM Corporation, Armonk in New York, USA). Absolute number and percentage were calculated for each validation question. Mean, standard deviation, minimum, and maximum were calculated for age. The other characteristics regarding demographics, and tumor disease were analyzed based on their respective absolute and relative frequencies.

Written informed consent was obtained from all study participants. Of the participants 49 were female and one was male. The 50 patients had an average age of 48 with a standard deviation of 14 years. The youngest one was 19 years old and the age of the oldest participant was 79 years. The data is not shown in detail. The validation process necessitates an assessment of the patients’ educational background, which is found to be a significant factor. The distribution of educational levels reveals that 15 patients (30%) possess a secondary school certificate, 10 (20%) have completed vocational training and 11 (22%) have obtained high school diploma. Notably 14 patients (28%) were academics, with three (6%) having attained a doctorate. In relation to current employment status, 23 patients (46%) reported full-time employment, while 11 patients (22%) indicated part-time work. The remaining 16% were retired,10% were homemakers and 4% were currently seeking employment ( Table 1 ). Doctorate University degree completed apprenticeship High School diploma secondary school certificate Full-time Part-time Retirement Housewife Jobseeking Upon consideration of the disease, distributions of patients into two groups of equivalent size are revealed, with one group consisting of patients with benign disease and the other with malign disease. The largest identified cohort is that of patients with breast cancer (20 patients; 40%) followed by those with cervical cancer (2; 4%) and ovarian cancer (3; 6%). Among participants with benign disease, endometriosis is the most frequently mentioned condition (20%). Furthermore, seven patients (14%) have been diagnosed with benign breast or pelvic floor disease or incontinence issues while one patient was present due to leiomyoma uteri ( Table 2 ). Breast cancer Cervical cancer Ovarian cancer Endometriosis Uterus myomatosus Benign leasion of the breast Pelvic floor/incontinence issues Forty-five out of fifty (90%) patients found the questionnaire easy to understand. Forty-seven participants (94%) felt that the time required to answer the questions was reasonable, two patients (4%) felt that the time taken was only partly appropriate and one (2%) thought that the required time was not reasonable. Almost all patients completed the questionnaire in less than 10 minutes. Exactly 21 of the respondents (42%) took less than five minutes, 24 others (48%) were able to complete the questionnaire in the additional minutes and reported a time of less than 10 minutes. Only five respondents (10%) took up to 15 minutes, with no respondents claiming to have taken more than a quarter of an hour ( Table 3 ). For the second part, the same inclusion and exclusion criteria applied as for the validation survey. Written informed consent was also obtained by all participants. In addition, a diagnosis of gynecological cancer was required, including endometrial carcinoma, ovarian carcinoma, cervical carcinoma or vulvar carcinoma. In total, data of 146 women treated in the outpatient clinic for genital cancers in the Women’s Hospital of the University Hospital Erlangen were analyzed. The mean age was 56 ± 14 years. The youngest patient was 19 years old and the oldest patient was 84 years old. The most common level of education was an apprenticeship (n = 64, 43.8%), followed by a secondary school certificate (n = 28, 19.2%) and a university degree (n = 22, 15.1%). The distribution of demographic characteristics is shown in Table 4 . Mean Standard deviation Minimum Maximum Habilitation Doctorate University Degree Apprenticeship High school diploma Middle school diploma Secondary school certificate No school-leaving certificate Patients with ovarian carcinoma constituted the largest group with 41% (n = 61). Patients with endometrial carcinoma (n = 33, 22.6%) and cervical carcinoma (n = 32, 21.9%) also participated in the study. The smallest group, but still 20 patients (13.7%) constituted the population suffering from vulvar carcinoma. Regarding disease status, approximately two-thirds (n = 94, 64.4%) had early carcinoma, while the remaining 35.6% (n = 52) had advanced disease. The type of treatment was also surveyed as an important parameter. The results indicated that the vast majority of patients with gynecological cancer had undergone surgery recently (47.9%, n = 70) or in the past (51.4%, n = 75). Only one patient reported not having undergone surgery (0.7%). Radiation therapy was applied by a smaller proportion, with 1.4% stating that they were currently receiving radiation therapy and 13.7% having received radiation therapy in the past. Thus, 84.9% reported that they had not received radiation therapy. Chemotherapy, an essential component of oncological therapy, was nut utilized in the treatment of 60.3% of the gynecological cancer patients surveyed (n = 88). Currently, 11% (n = 16) of respondents were receiving chemotherapy, and 28.8% (n = 42) had received chemotherapy in the past. Targeted therapy was part of the current treatment in 15.1% of patients (n = 22), and in the past in 11.1% (n = 16). However, in almost three quarters, (n = 108, 74.0%), no targeted therapy was applied. Endocrine therapy was rarely used in this population, with only 2.7% (n = 4) of patients currently using endocrine-based therapy and a further 2.1% (n = 3) having previously received it. 95.2% (n = 139) had not received any endocrine therapy ( Table 5 ). Ovaries Endometrium Cervix Vulva Early carcinoma Advanced carcinoma Surgery Radiation therapy Chemotherapy Targeted therapy Endocrine therapy In terms of lifestyle factors, it was observed that 84 patients (58.3%) had never smoked cigarettes, while 39 patients (27.1%) had smoked in the past. At present 21 patients (14.6%) were identified as smokers. Two patients did not disclose any information. When queried about alcohol consumption, 61.1% (n = 90) of the patients with gynecological carcinoma reported abstaining from alcohol consumption. Almost a third (32.9%, n = 48) reported drinking alcohol once or twice a week, 2.7% (n = 4) several days a week and 2.1% (n = 3) reported alcohol consumption on a daily basis. One person did not disclose any information. Almost all patients consumed fruit and vegetables nearly every day, (n = 133, 91.1%). Only a few patients reported fruit or vegetable consumption once or twice a week (8.2%, n = 2). When asked about the consumption of red meat specifically, 8.9% (n = 13) stated that they do not consume red meat. Consumption of red meat once or twice a month was reported by 28% (n = 42) with most patients consuming red meat once or twice a week (57.5%, n = 84). 4.8% (n = 7) of patients consume red meat almost on a daily basis. With respect to physical activity, 11 patients (7.5%) stated that they do not exercise regularly. 6.2% of patients (n = 9) answered with once or twice a week, 11.0% (n = 16) with three to five times a week and three quarters of patients (75.3%, n = 110) reported daily physical activity. When asked specifically about exercise that makes patients sweat, 44.5% (n = 95), almost half of the respondents, stated that they do not exercise. 36.3% of patients (n = 53) exercise once or twice a week, 9.6% (n = 14) three to five times a week. The same number of patients exercises daily (9.6%, n = 14). One person stated exercising only once or twice a month ( Table 6 ). No, never Yes, in the past Yes, currently Never 1–2 times a week 3–6 times a week Rather every day Never 1–2 times a month 1–2 times a week Almost daily/daily Never 1–2 times a month 1–2 times a week Almost daily/daily Not at all 1–2 times a week 3–5 times a week Daily Not at all 1–2 times a week 3–5 times a week Daily Participants were also asked about their complaints. The most commonly reported symptoms were “sleep disorder” (n = 40, 27.4%), “fatigue” (n = 34, 23.3%), “depressed mood” (n = 31, 21.2%) and “dry skin/mucous membranes” (n = 24, 16.4%). Less frequently, patients reported “pain” (n = 16, 11.0%), “hot flushes/menopausal symptoms” (n = 16, 11.0%), “reduced cognitive function” (n = 11, 7.5%) or “polyneuropathy” (n = 11, 7.5%). A total of 8 patients (5.5%) stated suffering from “diarrhea”. The most common complaints and their distribution by tumor localization are shown in Table 7 . Furthermore, patients were asked to select the CIM interventions they are using or have used. More than half of the patients (n = 81, 55.5%) named “sport/exercise”, as the most frequently used intervention. The second most commonly used intervention was vitamin D supplementation (n = 43, 2%). Based on the questionnaire, about 30% of the study participants described the use of chamomile (n = 47, 32.2%), green tea (n = 44, 30.1%), sage (n = 42, 28.8%) or massage methods (n = 42, 28.8%) each. Table 8 summarizes the most frequently mentioned CIM methods. The S3 guideline questionnaire divides CIM methods into three different categories according to the risk of interaction. In total, the use of a CIM method was described 267 times (multiple answers were possible). Most of these were in the green category with low risk (n = 124, 46.4%). Interventions in the yellow category with medium interaction potential were used slightly less frequently (n = 93, 34.8%). CIM methods of the red category with high risk were mentioned 50 times (18.7%. Fig. 1 shows the frequencies of the CIM categories overall and by tumor entity and stage of disease. Frequencies of utilization of CAM categories according to the S3 guideline questionnaire in total and per cancer entity; number of CAM methods n = 276.

Until now, there has been a lack of standardized questionnaires that explicitly ask about complementary medicine and integrative treatments. It has been shown that the questionnaire from the S3 guideline “Complementary Medicine in Oncology” is easy to understand and can be answered in a short time by patients who have already heard of these procedures or have informed themselves in this regard. The presentation of the level of education is intended to serve the transparency and classification of the validation. The result clearly shows that a broad section of the population can understand and answer the questionnaire very well. This means that it can be used on a broad scale. The inclusion of patients with benign diseases should also show whether the questionnaire is also understood in this group and can therefore possibly be adapted for use in other chronic diseases outside the oncological spectrum 19 20 21 (data from CIM use in chronical disease pain non cancer). The utilization of this questionnaire in routine clinical practice is a subject that merits deliberation, given its minimal effort requirements and its documented efficacy in enhancing patient comprehension. Furthermore, its capacity to mitigate the potential of interactions with antitumor therapy renders it a valuable addition to the therapeutic strategy. The utilization of the questionnaire is poised to expand in the future, which may result in patients posing content-related inquiries to attending physicians regarding the individual herbs or methods. However, it is important to note that physicians generally possess limited knowledge regarding complementary medicine interventions 11 . It remains to be further explored how targeted training of oncologists can be provided and what barriers must be overcome to further expand knowledge in the field. The introduction of the S3 guideline is a significant development for the evidence-based treatment of patients with cancer. However, the guideline also highlights a significant dearth of evidence for numerous applications, underscoring an urgent need for research to enhance the treatment of cancer patients. The utilization of questionnaires in clinical research in general, not only in the field of CIM, can be a very useful tool. Using a simple questionnaire, it is possible to obtain a good overview of the patient’s CIM methods and a direct classification. A notable finding is the underreporting of complementary medicine interventions used by patients 18 . However, this can have a substantial impact on therapeutic interventions and consequently on pivotal study objectives. Further research is necessary to substantiate the questionnaire’s clear benefits and ensure its precise implementation. One potential factor that merits consideration is the timing of the survey administration. A notable limitation of this study is its focus on complementary medicine use in Germany and Western Europe. Further research is needed to assess the questionnaire’s international applicability or the need for adaptation. Notwithstanding, the questionnaire can be used as a foundational instrument for the treatment of patients with other diseases, for which the hypothesis posits that the enhancement of quality of life and the active participation in recovery are pivotal to many disease patterns. However, the extent to which this can be transferred to oncology patients also requires further investigation. Finally, it should be noted that 49 of the 50 participants in the validation were women, as the survey was conducted at a gynecological clinic. Despite the high agreement and comprehensibility, further data are needed to assess gender-related differences in content validity and impact. The validation cohort was aimed at the broadest possible user group, which makes the statement of comprehensibility appear as universal as possible. Even though the group of patients with gynecological cancers was older on average and differed from the validation cohort in terms of the median burden of the disease, this played a minor role in the pure comprehension of the questionnaire. Older patients and cancer patients were also included here and yet almost all patients were able to understand the questionnaire. This allows the conclusion to be drawn that the disease-specific factors do not play a significant role here. A substantial body of research has already been amassed on the use of complementary medicine for breast cancer 22 23 , yet preliminary studies have indicated that the utilization of phytotherapy as a component of complementary treatment for gynecological cancers is comparatively infrequent 10 . A collective analysis of the treatment modalities employed in the management of ovarian carcinoma, endometrial carcinoma, cervical carcinoma and vulvar carcinoma reveals that surgery constituted the primary therapeutic approach in all cases. Almost every patient had undergone surgery, currently or in the past, only one patient reported no surgery (n = 1, 0.7%). Chemotherapy was part of the therapeutic regimen in about 40% of patients, while radiation therapy was administered to a smaller proportion of patients (15%). Even if only a third are in an advanced stage of the disease (n = 52, 35.6%), the majority of early-stage patients (n = 94, 64.4%) with gynecological cancer not only require extensive therapy, but the cancer itself is usually accompanied by physical impairments. This observation suggests that the etiology of numerous symptoms may be multifactorial, involving not only therapeutic interventions but also the underlying disease process itself, which plays a substantial role in the manifestation of patient complaints. Fatigue, depressive mood and sleep disorders were particularly salient among patients, who sought to manage symptoms with CIM. Only the collective was described in this study; a dedicated investigation of the relationship between symptom burden and intervention or CAM use was not examined. Future work could investigate this aspect in more detail. In this context, it has now been shown that 18.7% of patients utilize interventions that are classified as critical with a high interaction potential by the guideline committee, while the remaining 34.8% utilize interventions that are classified as medium critical regarding the interaction potential. The distribution exhibited high similarity across all entities. However, the most frequently mentioned interventions are not classified as critical in terms of interaction potential which can be considered clearly positive, with over 55% of patients reporting sports and exercise. This points to the knowledge of a healthy lifestyle and its influence on health even in the case of a tumor disease. The red category is regarded as particularly critical, as a statistically significant difference was identified when comparing early disease to advanced disease status. Of the 50 applications considered critical, 30% (n = 15) were in an advanced disease stage while 70% were in an early disease stage, corresponding to a p value of < 0.001 at a confidence level of 95%. Potential explanations include enhanced resilience and augmented physical and mental resources in the early stages, potentially allowing patients to engage in activities beyond the prescribed medication. However, this phenomenon also underscores a significant challenge, as the primary focus in such cases is on the response to therapy and the cure of a potentially fatal disease, often involving the use of numerous drugs in combination with questionable substrates which can pose potential risks to the patient. The observation that more than a third of the patients use potentially problematic interventions further reinforces the necessity for this questionnaire to be incorporated into routine oncological presentations. A distinguishing feature of this study is its use of a general collective as the surveyed population, which contrasts with many other studies that have opted for more targeted approaches 15 . This points out that a comprehensive and broad survey of complementary medical measures is necessary to ensure the safe and optimal treatment of patients. On the other hand, this implies that all medical practitioners must receive training to recognize potentially risky procedures and assess their safety. In future studies it would be beneficial to assess whether other patient populations should undergo similar evaluations or if the gynecological cancer population, which includes cases of severe illness, constitutes an exception to this assessment. Limitations of the study include the single-center design and the potential influence of locoregional characteristics that cannot be ruled out. Additionally, a consultation for integrative medicine is offered at the same clinic, which could introduce a bias in the survey. Furthermore, the survey exclusively involved women; a survey of a male population could potentially yield different result regarding the questionnaire’s validation.

The use of complementary medicine is far from being a niche in oncology but is practiced by a large proportion of patients. Some published data suggest that 50% of all cancer patients use complementary medicine, while other data show that the percentage is even higher 1 2 . Complementary medicine constitutes an additional therapy or method that is intended to support conventional cancer therapy. Among the various interventions that have been established are acupuncture, meditation, use of herbs and nutritional supplements. A recent meta-analysis has indicated a general increase in the popularity of such interventions over the last few decades 3 . It is imperative to make a clear distinction between the term “complementary” medicine and the term “alternative” medicine. The latter pertains to therapies that are utilized in lieu of conventional cancer therapy 4 . If the various therapeutic approaches merely run in parallel without being coordinated, possible interactions represent a risk for patients’ safety 5 . Interactions can manifest themselves not only in the form of toxicity, but also in a potentially lower effectiveness of the therapy 6 7 . Gynecologic oncology has undergone significant changes in recent years, with many new therapeutic agents flooding the market and new therapeutic approaches that have significantly improved life expectancy 8 9 . As a result, the patient population is being treated for extended periods of time and a substantial increase in the utilization of complementary medicine can be anticipated. In a previous analysis, the utilization of phytotherapeutics in patients diagnosed with gynecological cancers was examined. In this particular study, 40% of the patients in the aforementioned group indicated that they were consuming herbal medicines for medical purposes 10 . The extent to which this result can be confirmed and what further procedures can be used by this population, many of whom are seriously ill, remain to be ascertained. Conversely, a considerable degree of skepticism and ignorance is evident within the medical profession regarding CIM interventions 11 . Patients thus frequently use complementary medicine interventions without consulting their doctor 6 . This may result in an increased risk for patients, including reduction of success of oncological therapies and increased harmful side effects 12 13 . It is common sense that action is required to improve the care of oncology patients in the field of complementary medicine. Therefore, research into the development of better evidence for CAM has been ongoing on a global scale for a number of years 14 . Despite the establishment of dedicated consultation hours for integrative medicine at several centers, its utilization within the everyday clinical practice remains minimal 11 15 . Some of the patients may utilize one or more of the aforementioned CIM interventions as part of a lifestyle considered healthy. Furthermore, it is recognized that others may have medical conditions or issues that result in the use of one of the listed interventions or supplements 10 . For the first time, an S3 guideline on complementary medicine in oncology was published in 2021 16 . A comprehensive overview of the field of CIM was presented with the highest level of evidence being accorded to the respective established methods and recommendations being made in the cases where sufficient data was available. In line with expectations, the guideline also revealed a paucity of satisfactory data on the incoherent use of complementary medicine interventions, even for widely used procedures. The guideline commences with a presentation of archetypal symptoms experienced by patients undergoing oncological therapies. For this, recommendations are given directly assigned to individual symptoms. The subsequent part of the guideline comprises a compendium of the most commonly utilized interventions each followed by a statement. In instance where negative data is available, the term “should not be made” is employed. This level of recommendation is hitherto unparalleled in other oncology guidelines within Germany. The objective is to distinctly differentiate potentially hazardous interventions and enhance patient safety. Therefore, a simple questionnaire was designed for this guideline, for the purpose of recording the use of complementary medicine interventions in oncology patients in a structured manner 16 . The most common phytotherapeutics, vitamins, nutritional supplements and dietary recommendations as well as sports and exercise therapies are queried, for details have a look at the appendix Fig. S1 (online).

Fig. S1 : The complete questionnaire from the S3 guideline complementary medicine in clinical oncology.