Holistic Evaluation of Approaches to Long-term Health & Survivorship

1. OBJECTIVES The study's objective is threefold including quantitative, qualitative and operational objectives

   1.1. Primary objectives (Quantitative - phase 1)

   The goal of the quantitative analysis is to provide objective insights into various aspects of patient behavior and need, including :

   • Measuring and quantifying usage patterns to determine who takes what kind of CAMs in what purpose ;
   • Objectively analyzing behaviors to identify trends and variations across different patient groups ;
   • Assessing and defining patient needs and information sources to better understand gaps in care and areas for improvement.

   1.2. Secondary objectives (Mixed-methods - phase 2)

   The qualitative analysis aims to provide a deeper understanding of patient behaviors, decision-making processes, and contextual influences, including:

   • Observation and assessment of current practices ;
   • Understanding behavioral patterns in different contexts ;
   • Prioritizing needs and expectations ;
   • Developing an integrative guidance system supporting patient treatment adherence ;
   • Identifying significant roles in guiding patients toward CAM.

   Post-interview qualitative analysis: Following qualitative interviews, additional insights will be gathered to evaluate:

   • The perceived benefits of the session and whether patients express interest in further need ;
   • Any potential behavioral changes resulting from the discussion ;
   • Whether new connections or influences emerged after the interview. In addition, a structured medication review will be conducted for all participants in the focus group phase in order to identify and describe drug-related problems, including potential interactions between conventional treatments and herbal products. Drug-related problems will be classified using the PCNE Classification for Drug-Related Problems (version 9.1).

   1.3. Exploratory and Operational Objectives The operational objectives focus on identifying needs, preferences, barriers and opportunities in the framework of ONCO.CARE and CAIROS project. The results will help conceptualize the patientpathway in integrative oncology and the content of the survivorship plan, in the specific frame of CAM's.

   1.4. Endpoints

   Primary Endpoints (6 months) :

   • Quantification of CAM consumption among patients at Bordet ;
   • Identification of unmet needs regarding CAM use and patient guidance ;
   • Assessment of treatment adherence when integrative medicine is used alongside conventional oral therapies.

   Secondary Endpoints (3 months) :

   • Enhancing patient empowerment within a safe and structured framework ;
   • Improving quality of life and supporting patients in managing the (long-term) side effects of cancer treatments ;
   • Prioritizing key objectives for the development of the survivorship program within the ONCO.CARE project, with a specific focus on CAM ;
   • Identifying essential elements for designing integrative care pathway within the CAIROS project, with a specific focus on CAM.
   • Identification and descriptive characterization of drug-related problems, including their number and type, classified according to the PCNE Classification for Drug-Related Problems (version 9.1).

   Exploratory Endpoints (3 months) :

   • Assessing the training needs of Bordet HCPs in the field of CAM ;
   • Providing clinical research data on CAM usage among Bordet patients to guide fundamental research in pharmacology faculty on the quality and composition of plant-based dietary supplements.
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 2.1. Medical Background Collaborators within the institution and literature show the important use of alternative and complementary medicine (CAMs) by cancer patients. In Europe, CAM use is quite clear.

A study in Sweden published in 2023 on 630 patients entering palliative care shows that 54% of them used CAMs. A US study from 2023 indicates that cultural aspects influence uses. For 658 cancer patients treated in New York, the prevalence of CAM use was 66.1%. CAM use was 71.9% in females and 54.3% in males. Patients of African descent had higher CAM use (72.7%) than the White patients (63.5%). Latin-American-born had a numerical trend toward higher CAM use (74.8%). The number of years of living in the United States was not associated with more CAM use. Another study from the Netherlands from 2023 shows that if health professionals are concerned about CAM use, they are helpless to supervise these practices. Out of 77 healthcare professionals responded to the questionnaire. In this study, 87% of them respond it is important to be aware of their patient's CAM use, and all find the potential of herb-drug interactions important. However, more than half inquire about the patient's CAM use infrequently. In addition, only 15% of them stated they had sufficient knowledge of CAM to advise patients on their use of CAM.

Our preliminary study in Belgium collected 349 online questionnaires (4 months long in 2020/2), but only 59 met all inclusion criteria. 83.1% of the patients agreed that conventional medicine could benefit from CAMs, but patients did not estimate (72.3%) that CAMs are more effective than conventional medicine. More than half of the patients used five or more natural products. The most frequent daily use were vitamins (64.4%), followed by other products (i.e., probiotics, gemmotherapy, birch sap, and omega 3/6) (42.4%) and herbs (40.7%). Almost all patients started taking natural products before their cancer diagnosis, but 72.7% have changed their consumption significantly since their diagnosis. Boosting the immune system (79.7%) and limiting conventional treatment side effects (76.9%) were the most common reasons for NHPs' use. 74.4% of the patients did not take complementary therapies to delay or avoid conventional treatment.

In Bordet specifically, a survey in 2023 amongst cancer patients indicated a strong interest, with a large majority of the female respondents (66%) mainly treated for breast cancer (65,3%). 55,6% of the users resort to more than one CAM (Body mind techniques (37,8%) and herbs/supplements (31,8%) are mostly used. Several respondents expressed the need for more secure information regarding the use of CAMs and the desire for a clear indication from their oncologist (abstract MASCC conference, Echterbille et al. 2024). Amongst Bordet's healthcare professionals, 85% find integrative oncology necessary but all of them request additional information to guide properly patients like a practitioner directory grouping integrative therapists (100%), education or training (85%), and evidence-based information on CAMs (30%) (abstract MASCC conference, Echterbille et al. 2024). Indeed, medical curricula lack training in non-conventional medicine including integrative medicine or use of CAM's.

In pioneering organizations in this field like Institut Gustave Roussy (Paris) or MSKCC Institute (New York), clinical pharmacists are responsible for providing bedside guidance. Such guidance is not yet available in Bordet institute. On the website of the MSKCC institute (New York), you can read: " Some people take herbs and dietary supplements in addition to medications. Here are important guidelines that you must follow when taking supplements.

• Stop taking all herbs and supplements 1 week before having a procedure or surgery, or as directed by your doctor. Some herbs may interfere with anesthesia or with blood clotting.
• Ask your healthcare provider or a doctor in the Integrative Medicine Service if you can keep taking an herb or supplement during your treatment. Some herbs or supplements may affect your treatment." To our knowledge, there is no published literature reporting the impact of CAM on oncology patient compliance. There is some data on diabetes where 7,000 patients were enrolled. This study did not show statistical significance in any of the 4 outcomes analyzed (influenza vaccination, eye examination, glycated hemoglobin measurement and foot exam). Another recent French study concerning a follow-up process involving pharmaceutical consultations (PC) in 32 patients undergoing oral anticancer therapy shows that these interventions have a positive impact on global health. A drug balance is carried out before the PC and then analyzed. The developed PC provides new elements related to the recommendations and allows a follow-up of the patient with toxicities that weaken his management along his therapeutical pathway. For more patient-based analysis, integrative aspects are to be considered. As pharmacists, the investigators will focus on therapeutics.

Moreover, this study is a preliminary need to further prioritize key objectives for developing the survivorship program within the ONCO.CARE project and in the integrative care pathway linked to the CAIROS project, in the specific frame of CAMs.

2.2. Drug Profile Not applicable. This study does not involve the administration, modification or evaluation of any investigational medicinal product or drug intervention.

2.3. Rationale This study will advance the state of the art in integrative oncology and survivorship care by providing empirical evidence on cancer patients' use of complementary and alternative medicine (CAM). It will also inform clinical practice by identifying gaps, needs, and opportunities for structured CAM integration into oncology care.

Key Contributions to the Field :

1. Evidence-Based Insights on CAM Usage : By quantifying who uses CAM, for what purpose, and in what context, this study will offer objective data that is currently insufficient in oncology care.
2. Understanding Patient Decision-Making and Needs : The qualitative component will provide in-depth insights into patient behavior, motivations, and barriers, which can help guide clinicians in addressing patient concerns more effectively.
3. Informing Integrative Oncology Strategies : The results will support the development of structured guidance for oncologists and healthcare providers on how to discuss and integrate CAM within standard cancer treatment plans.

Impact on Clinical Practice :

1. Enhanced Patient-Centered Care : By identifying patient expectations and concerns, the study will contribute to improving doctor-patient communication and fostering a more patient-centered approach in oncology.
2. Structured CAM Integration in Survivorship Programs : The findings will help design a clear framework for CAM use in survivorship programs within ONCO.CARE and CAIROS, ensuring that CAM is used safely and effectively alongside conventional treatments.
3. Potential Policy and Guideline Development :

If the study highlights significant trends and unmet needs, it could lead to new recommendations or guidelines for CAM integration in cancer care, shaping future clinical practice.

Pharmaceutical Perspective and Safety Considerations :

The increasing use of complementary and alternative medicine, including natural health products and herbal therapies, raises important questions regarding safety, efficacy, and potential interactions with conventional cancer treatments. In this context, integrating a pharmaceutical perspective is essential to better characterize and manage risks associated with CAM use. This study will contribute to identifying drug-related problems, including potential interactions and safety concerns, and will provide a structured approach to support safe and informed use of complementary therapies in oncology. This approach highlights the role of pharmaceutical expertise in improving treatment safety, optimizing patient counseling, and supporting evidence-based integrative care.

By bridging the gap between patient needs and clinical practice, this study will help advance the field of integrative oncology and improve the quality of survivorship care.

3. INVESTIGATIONAL PLAN 3.1. Design

1. Quantitative evaluation of cancer patient's use of CAM's : A survey will be distributed to cancer patients over a three-month period to assess their use of complementary and alternative medicine (CAM). The questionnaire will be accessible through non-intrusive methods, including dissemination via healthcare professionals, display of study information and QR codes on hospital screens or in waiting areas, and access via a secure online link (REDCap). The survey will be available in both paper format and online via QR code (REDCap). The paper versions of the survey will be collected in a dedicated box at the entrance of the Bordet building. The questionnaire is fully anonymous, and no directly identifiable personal data will be collected. Data treatment will be processed by Delphine Thénevin supervised by Florence Horicks \& Florence Souard.

   The questionnaire collects self-reported data related to patients' medical history (e.g. type of cancer, treatments received, associated symptoms), use of complementary and alternative medicine (CAM), motivations for use, perceived benefits and risks, sources of information, and interest in integrative care programs. In addition, basic sociodemographic data (age, gender) are collected.

   Geographic data (province of residence) are collected to explore potential regional differences in access to CAM resources, healthcare services, and information mainly the differences between rural and urban areas and also the differences between the three regions of Belgium. Self-identified ethnocultural background is collected on an optional basis to explore potential variations in health behaviors, particularly in the use of CAM and access to related information. Existing literature, including WHO reports on traditional and complementary medicine, suggests that health practices and the use of complementary approaches are influenced by cultural context1. Collecting these variables may therefore help explore potential variations in CAM use, access to information, and patient needs. Furthermore, the inclusion of a health literacy questionnaire in the quantitative component is not feasible. Nevertheless, the ethnocultural data are expected to offer important insights into the social determinants shaping behaviors toward complementary and alternative medicines (CAMs).

   All data are self-reported, collected anonymously and will be analyzed in aggregated form.

2. Interventional mixed-methods evaluation of cancer patient's behaviour regarding CAMs : Participants will be recruited through collaborations with treating healthcare professionals and institutional communication channels. Patients will be invited to participate in focus group sessions lasting approximately two hours, with a maximum of eight participants per session. The investigators will conduct a proof-of-concept study over six months, organizing one to two focus groups per month. This work will provide sufficient data to support and design of the survivorship program of ONCO.CARE project (for CAMs field). If this initial period yields conclusive results - defined as at least one-third of participants reporting the use of natural health products and actively seeking information - the focus groups will be extended. Regardless of the outcome, these preliminary sessions will provide valuable insights into the use of CAM as supportive care among Bordet patients.

Before each session, participants will receive an anonymous questionnaire (attached). Geographic data (province of residence) are collected in pre-focus group questionnaires, to explore potential regional differences in access to CAM resources, healthcare services, and information.

The focus groups will begin with a presentation of the project followed by a discussion where participants will be encouraged to share their experiences. Focus group sessions will follow a semi-structured methodology with the help of an interview guide developed by the research team.

The discussion guide is structured into several thematic sections, including:

• introduction and presentation of the study framework,
• exploration of participants' knowledge and use of complementary and alternative medicine (CAM),
• motivations and perceived benefits,
• perceived risks, concerns and barriers,
• sources of information,
• needs and expectations regarding integrative care and survivorship. Interactive techniques (e.g. visual supports or mapping exercises) may be used to facilitate discussion and participant engagement.

A standardized introduction will be provided at the beginning of each session, and participants will be informed of the framework and limits of the discussion. Group interaction will be encouraged while ensuring respectful and confidential exchanges between participants.

Sessions will be audio-recorded with participants' consent, transcribed verbatim, and analyzed using rapid qualitative analysis methods.

The investigators aim to explore :

• Patient's behavior and consumption of CAMs ;
• Patient's motivations for using CAMs in their care follow-up ;
• Their specific objectives in using CAM during treatment ;
• The actions the participants take to manage therapy-related issues, such as side effects from hormone therapy, late adverse effects of chemotherapy or radiotherapy, etc ;
• Patient's sources of information regarding CAMs Each focus group will be conducted by at least two investigators: one responsible for qualitative data collection and one phytotherapy expert to ensure CAMs consumption safety .

In addition, a structured medication review will be conducted for all participants included in the focus group phase. This review will be based on self-reported treatment data and relevant information from the medical record, in order to identify and describe drug-related problems, including potential interactions between conventional cancer treatments and herbal products. Drug-related problems will be classified using the Pharmaceutical Care Network Europe (PCNE) Classification for Drug-Related Problems (version 9.1). Access to relevant medical records will be required for participants included in the medication review component.

If a potential clinically relevant drug-related problem or interaction is identified during the medication review, this information may be communicated to the participant and, where appropriate, to the treating physician, in accordance with good clinical practice and with the participant's consent.

Following the focus group, quantitative and qualitive data will be analyzed. Participants will complete pre- and post-focus group questionnaires (paper or online via QR code).

The ultimate goal of this study is to prioritize key objectives for developing the survivorship program within the ONCO.CARE project, in the specific frame of CAMs.

3.2. Description of population For quantitative survey: any cancer patient entering the Bordet Institute. Minimum 500 patients. A survey will be completed by cancer patients over a three-month period to assess their use of complementary and alternative medicine (CAM).

For interventional mixed-methods study : cancer patients (men and women) after acute phase of anti-cancer treatmentThis study will include a total of 6 to 8 focus groups, with each group consisting of 5 to 10 participants. So, a total of 30 to 60 participants is expected.

3.3. Strategies for participant recruitment A survey will be made available to cancer patients over a three-month period to assess their use of complementary and alternative medicine (CAM). Recruitment will be conducted through non-intrusive methods, including:

• dissemination of study information via healthcare professionals,
• posters or flyers containing QR code displayed in appropriate waiting areas,
• display of a QR code on hospital screens,
• access to the questionnaire via a secure online link or QR code. Participation is entirely voluntary, and patients may choose to complete the questionnaire at their own discretion. Participants will receive an information page at the beginning of the questionnaire (REDCap), detailing the study objectives, voluntary nature of participation, anonymous data collection, and data use. Proceeding to the questionnaire will be considered as provision of informed consent. Moreover, the questionnaire will start by mentioning the GDPR rules and participants have to agree with it. If the participants don't, the questionnaire will end immediately. Participants for the focus group sessions will be recruited through non-intrusive methods, including institutional communication channels (e.g. posters or flyers displayed in appropriate areas of the hospital) and collaboration with treating healthcare professionals. At the end of the quantitative questionnaire, participants will have the opportunity to express their interest in the focus group phase and to contact the study team voluntarily via the investigator's email address. In addition, dedicated study flyers will be made available within the institution, providing contact details of the study team and a QR code allowing participants to directly generate a pre-filled email to request further information. These flyers may also be handed to patients by healthcare professionals as part of routine care, without any direct solicitation or obligation to participate. Patients who express interest in participating will either contact the study team directly or agree to be contacted for further information. The participants will receive the ICF upfront and be offered the possibility to contact the team for any question regarding their participation. Participation in focus groups is entirely voluntary. Written informed consent will be obtained from all participants prior to participation in this phase.

3.4. Participants eligibility 3.4.1. Inclusion criteria

For quantitative survey :

French speaking patient entering Bordet Institute.

For interventional mixed-methods study :

French speaking adult cancer survivor patients who have completed active cancer treatment. Individuals in remission or undergoing long-term long term oral therapy.

3.4.2. Exclusion criteria

For quantitative survey:

• Not to have or have had cancer ;
• Have already answered to this survey before.

For interventional mixed-methods study :

Patients currently undergoing active cancer treatment 3.4.3. Withdrawal Participation in this study is entirely voluntary. Participants may withdraw from the study at any time and for any reason, without having to provide justification and without any impact on their medical care or relationship with the healthcare team. Participants may be withdrawn from the study for the following reasons :

• Voluntary withdrawal of consent by the participant ;
• Inability or unwillingness to comply with study procedures ;
• Decision by the investigator that continued participation is no longer appropriate ;
• Early termination of the study by the sponsor or by the competent Ethics Committee for scientific, ethical, or organizational reasons. No specific follow-up is planned for participants who withdraw from the study, as this is a minimal-risk, non-medicinal study with no therapeutic intervention.

3.5. Treatments Not applicable. This study does not involve any therapeutic intervention.

3.6. Safety Reporting Given the non-interventional nature of the study and the absence of any investigational medicinal product, invasive procedure or therapeutic intervention, no systematic collection of adverse events (AEs), serious adverse events (SAEs) or SUSARs is planned.

The study activities are limited to questionnaires and focus group discussions, which are associated with minimal risk.

3.7. Site Monitoring Plan Site monitoring is conducted to ensure the human subject protection, study procedures, laboratory, study intervention administration, and data collection processes are of high quality and meet sponsor, GCP/ICH and regulatory guidelines.

Given the non-medicinal, minimal-risk nature of this study, no formal on-site monitoring visits are planned.

Study oversight will be ensured through internal monitoring conducted by the study team and the sponsor, focusing on:

• Compliance with the approved protocol and Ethics Committee approval;
• Appropriate informed consent procedures;
• Adherence to inclusion and exclusion criteria;
• Proper conduct of study procedures (questionnaires and focus group sessions);
• Data completeness and consistency in REDCap. Monitoring activities will be primarily conducted centrally, through regular review of study documentation and REDCap data by authorized members of the study team and sponsor.

If specific issues are identified, targeted corrective actions may be implemented, and additional review may be performed as needed.

3.8. Data Quality Assurance 3.8.1. Quality control

Throughout the study the dedicated sponsor study team members verify the data to ensure that:

• The rights and well-being of subjects are protected ;
• The reported trial data are accurate, complete and verifiable from source documents ;
• The conduct of the trial is compliant with the applicable regulatory requirements, the study protocol and the study guidelines.

Monitoring activities may be performed remotely, according to the needs of the study.

3.8.2. Quality assurance Given the academic and non-medicinal nature of the study, no routine quality assurance audit is planned. However, the sponsor reserves the right to conduct a quality assurance review or audit of the study site if deemed necessary. In addition, the study may be subject to inspection by competent authorities or institutional oversight bodies, in accordance with applicable regulations.

In the event of an audit or inspection, the investigator and institution agree to provide direct access to relevant study documentation and to cooperate fully with the auditors or inspectors, in compliance with confidentiality and data protection requirements.

3.9. Statistical Analysis The objectives of both the quantitative evaluation of cancer patient's use of CAM's by a survey and the interventional mixed-methods evaluation of cancer patient's behaviour regarding CAMs by organizing focus groups are exploratory. The sample size for the survey and the number of focus groups are determined by the feasibility of this study. Currently a total of 500 patients in the survey and 6-8 focus groups are planned. The feasibility of the survey will be assessed after 50-100 patients are recruited. The total number of patients recruited might be calibrated during the study to include more patients in the under-represented subgroups of interest.

Quantitative data analysis:

The results of the survey will be analyzed statistically using descriptive statistics . The investigators aim to analyze the socio-demographic characteristics of participants, objectify their use of CAM's and collect quantitative information on their unmet needs.

Exploratory analyses may be conducted to assess potential differences in CAM use according to demographic and sociocultural variables, including province of residence and self-identified ethnocultural background. CAM use will also be compared between cancer types, cancer stages, treatment types, and time since diagnosis.

Chi-square or Fisher's exact analysis will be used to analyse categorical variables to compare between subgroups. Similarly, Wilcoxon or Kruskal-Wallis test will be used to analyse continuous variables. Univariate logistic regression will be used to obtain the odd ratios of taking certain CAMS. When appropriate, covariate adjustments will be applied using multivariate regressions. Paired tests will be used to analyse two data points within the same patients. Longitudinal data will be analyzed using mixed models.

For Phase 2, pre- and post-focus group questionnaires will be analyzed descriptively and separately; no paired, comparative, inferential analyses will be performed.

Health literacy data collected via REDCap during the phase 2 will be analyzed descriptively.

Drug-related problems identified through medication review will be analyzed descriptively, including their number and type, and classified according to the PCNE Classification for Drug-Related Problems (version 9.1).

Qualitative data analysis:

The interviews and the focus group will be recorded, transcribed, and analyzed by two team members. Transcripts will not be returned to participants for comment or correction.

Interview and focus group data will be analyzed using rapid qualitative analysis. Rather than producing deep theoretical insights, this pragmatic method identifies or enhances our understanding of key intervention elements, facilitators, and/or barriers in response to time-sensitive research implementation questions. The matrix method will be used to systematically summarize the data and analyze by case and code. Rigor and validity will be mainitained by independently assigning data in the matrix and discussing differences.

4. STUDY PATIENTS 4.1. Disposition of patient A clear accounting of all participants who enter the study will be maintained. For Phase 1 (quantitative observational survey), the number of participants who complete the questionnaire will be reported.

For Phase 2 (interventional mixed-methods study), the following information will be documented:

• Number of participants who consented ;
• Number of participants who attended a focus group session ;
• Number of participants who completed the pre- and post-focus group questionnaires ;
• Number of participants who discontinued participation prior to completion. The investigator has the right to discontinue a subject from the study treatment or withdraw a subject from the study at any time. The subject has also the right to discontinue the study treatment or withdraw from the study at any time without giving their reasons. Although a subject is not obliged to give his/her reason for withdrawing prematurely from the study treatment or the complete study, the investigator should make reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.

Reasons for discontinuation from the study may include, but are not limited to:

• Subject's/ subject parent/legal guardian's request/consent withdrawal ;
• Investigator, sponsor or competent authorities determine it is in the best interest of the subject ;
• Inability or unwillingness to attend or complete study procedures (e.g. focus group session) ;
• Early termination of the study by the sponsor or the competent Ethics Committee.

Participants who discontinue participation will not be replaced. When available, the reason for discontinuation will be documented in the study records in an anonymized or pseudonymized manner.

No medical follow-up is planned for participants who discontinue participation, as this is a minimal-risk, non-medicinal study with no therapeutic intervention.

4.2. Patient follow-up No clinical follow-up is planned as part of this study. Participants will receive standard medical care according to institutional practices, independent of their participation in the study. No additional care or follow-up is required as a result of study participation.

However, participants will be provided with the contact details of the investigator and study team if they have any questions or require further information following their participation.

5. END OF TRIAL Estimated Duration and End of Each Study Phase Phase 1 : quantitative observational survey) The end of Phase 1 is defined as the date on which the quantitative survey is closed, after a minimum recruitment period of 3 months and the inclusion of at least 500 participants.

Phase 2 : Interventional mixed-methods phase The interventional phase will be conducted over a period of six months, during which six to eight semi-structured focus group sessions will be organized. Each participant will attend one focus group session only, with an estimated duration of 2 to 3 hours per session The end of Phase 2 is defined as the completion of the planned focus group sessions and the observation of data saturation, in accordance with qualitative research standards.