This phase II, parallel group, randomized controlled trial compared the effectiveness of IOD-CAM with SC in reducing adverse events (AE) in patients undergoing oncology treatment and care. The study was prospectively registered with ClinicalTrials.gov (NCT03857776) and approved by the Danish Data Protection Agency through the Region of Southern Denmark (19-4309). According to the Committee on Health Research Ethics, their approval of the study was not required (15/42744). The protocol was not amended during the study, and since it did not involve any risks to the patients, no interim analysis was done. The study is reported according to the CONSORT guidelines .
The study was conducted at the Oncology Outpatient Clinic, Vejle Hospital, University Hospital of Southern Denmark, between April 2019 and July 2020. The Department of Oncology offers treatment and care to adult patients with breast, gynecological, prostate, pulmonary, colorectal, anal, and pancreatic cancer. There are around 57,000 outpatient visits to the department each year with 23,000 radiotherapy fractions and 9,300 chemotherapy and immunotherapy treatments administered.
The inclusion criteria were ≥18 years of age, diagnosis of primary cancer or recurrence within the last three months, planned antineoplastic treatment (chemotherapy, immunotherapy and/or antibody therapy), realistic plan of at least two months of treatment, and life expectancy of six months. The ability to read and speak Danish was required. The exclusion criterion was participation in other trials interfering with the intervention or data collection. Eligible participants were informed and invited to participate in the study by health professionals prior to the first cycle of treatment in the outpatient clinic. Randomization onto the study was based on written and orally informed consent.
Intervention group (IOD-CAM)
In addition to SC, patients in the intervention group participated in one or two sessions of IOD-CAM facilitated by a nurse specialist. A primary caregiver participated, if preferred by the patient. The guideline for IOD-CAM presented in Figure 1 was inspired by the Andrew Weil Center for Integrative Medicine, University of Arizona and Schofield et al.’s recommendations [26, 28].
Control group (SC)
Patients randomized to the control group received SC and referral to www.kabcancer.dk, a website presenting research based information about potential effects and outcomes of CAM. SC was defined as oncology treatment and care, including antineoplastic drugs at the outpatient clinic. SC also involved continuous assessment of the patients’ performance status, side effects, and symptoms, which were managed by specialist doctors and nurses.
Based on written, orally informed consent, and subsequent baseline assessment, the patients were randomly assigned to either SC plus IOD-CAM or SC alone. Randomization 1:1 was computerized using Research Electronic Data Capture (REDCap) . The study nurse informed the patients about the allocation. Patients randomized to IOD-CAM received a letter providing the date, time, and place for the IOD-CAM session and guidance for preparation. Patients randomized to SC received a pamphlet referring to the website www.kabcancer.dk.
Due to the nature of the intervention, neither patients nor staff were blinded to the allocation, but patients were strongly encouraged not to disclose the allocation status at the follow-up registration of adverse events.
Outcome measures and data collection
The primary outcome measure was the frequency of grade 3-4 AEs eight weeks after enrollment. The frequency of grade 0-4 AEs 12 and 24 weeks after enrollment were secondary outcome measures. At each follow up (8, 12 and 24 weeks), patients’ AEs were registered by a specialist nurse according to the Common Terminology Criteria for Adverse Events (CTCAEv5) . We have registered the severity of 15 common AEs, i.e. dry mouth, oral mucositis, vomiting, nausea, constipation, diarrhea, pain, peripheral motor neuropathy, peripheral sensory neuropathy, fatigue, fever, febrile neutropenia, infections, hospitalization, and general discomfort. The secondary outcome measures included patient reported QoL, level of depression and anxiety, and perception of received information 12 and 24 weeks after enrollment.
To assess QoL, the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30)  was applied. It includes five functional scales, nine symptom scales and two global QoL scales. Patients’ perception of information received was assessed using EORTC QLQ-INFO25 . It consists of 26 items organized in four hypothesized scales; information about the disease, medical tests, treatment and other services, and eight single items. The level of depression and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS), which is a self-assessment scale composed of 14 items on two subscales assessing anxiety and depression symptoms in the past week . The patients’ use of and attitude towards CAM 24 weeks after enrollment was also measured. All questionnaires were administered electronically.
The study is a randomized phase II screening trial  with a risk of type-1 error at 0.10 and a power of 0.80. It was hypothesized that 25% of the patients in the IOD-CAM group would have grade 3-4 AEs eight weeks after enrollment compared to 50% in the SC group. Under these circumstances, 92 patients were required. To account for dropouts, the total number of patients to be enrolled was 106.
The two groups were compared in all primary analyses. Demographic data are presented as counts (n) and proportions (%), respectively, with means and standard deviations (SD). Chi-square test and Fisher's exact test was applied to detect differences between the two groups in relation to AEs. The EORTC QLQ C30 and INFO25 scores were reported as means with confidence intervals, and HADS scores as medians with 25th-75th percentiles. Comparison of the two groups relied on Student's t-test or Mann Whitney’s U test.
P-values are reported to two decimal places. For the primary endpoint, two-sided p-values were used with a 0.10 level of significance. A professional academic statistician blinded to the study group assignment conducted all analyses.