Chronic cancer-related fatigue (CCRF) is a common symptom among patients treated with curative [1-4] as well as palliative intent [5-7]. It can persist for many years and has a profound negative impact on patients’ quality of life [2,8,9]. Its etiology is likely multifactorial and includes several biological pathways [10,11]. According to the cognitive-behavioral model of CCRF, cancer and its treatment initially trigger fatigue, while cognitive-behavioral variables (eg, negative cognitions about fatigue and disrupted activity patterns) explain its persistence after completion of treatment [12-14]. Based on this model, cognitive-behavioral and mindfulness-based therapies have been developed to address CCRF. While these and other interventions have been shown to effectively alleviate patients’ fatigue [15-19], they are directed at the patient with cancer alone, despite growing evidence for the importance of involving patients’ partners in the treatment of CCRF (ie, a couples’ approach to treatment).

CCRF is experienced in the context of patients’ close relationships in multiple ways. First, the way patients and their partners interact in daily life is related to patients’ fatigue outcomes. For example, a daily diary study among survivors of cancer and their partners showed that partners’ facilitative reactions (eg, encouragement to be active) were related to better fatigue outcomes, while solicitous reactions (eg, taking over the patient’s chores) as well as ruminative conversations—fueled by patients and their partners maladaptive cognitions—were related to worse outcomes during the day [20,21]. This suggests that interventions encouraging adaptive daily interactions between couple members have the potential to contribute to better fatigue outcomes for the patient. Second, the degree to which patients benefit from cognitive behavioral therapy for fatigue appears to be related to partner and relationship variables. That is, a recent study [22] among patients with chronic fatigue syndrome showed that relationship dissatisfaction among patients and high fatigue in their partners are associated with less improvement in fatigue severity after therapy. Third, ample research shows that the cancer experience also impacts intimate partners. In particular, partners have been shown to experience substantial distress [23,24], which is positively related to patient fatigue [25,26], suggesting that an effective fatigue intervention can also benefit partners. Fourth, the aforementioned diary study [20] suggests that the way a partner deals with fatigue in the couple’s daily life is not only related to fatigue outcomes but also patients’ relationship satisfaction, with solicitous and facilitative responses being related to higher relationship satisfaction. Jointly, the evidence suggests that targeting the couple instead of the patient alone has the potential to increase the intervention’s effect on patient fatigue and broaden its impact to alleviate partner distress and benefit the couple’s relationship.

Based on this and studies indicating beneficial effects of interventions for couples coping with cancer in general [27-30], the study team has developed a couple intervention for dealing with CCRF called COMPANION (Dutch: Samen Minder Moe). The intervention is based on a web-based mindfulness-based cognitive therapy (eMBCT) that has been shown to be effective in reducing patient fatigue [31].

Given the relative novelty of this interventional approach, conducting a pilot trial is warranted. The primary aims of this pilot trial are (1) to determine the acceptability of the couple intervention and (2) to investigate its potential efficacy in reducing patient fatigue. Secondary aims are (3) to examine the feasibility of the trial procedures and (4) to determine the potential working mechanisms of the couple intervention.

This study is a single-arm pilot trial among patients with cancer with CCRF and their partners. All included couples will be allocated to receive the COMPANION intervention, with a planned duration of 15-20 weeks. Couples will complete questionnaires and weekly diaries. Trial participation is estimated to take 6-8 months in total. Figure 1 presents a flowchart of the study.

Eligible participants are couples in which one member was diagnosed with cancer, completed cancer treatment for at least 3 months (excepting hormone therapy), and has been experiencing severe fatigue for at least 3 months. See Textbox 1 for an overview of all inclusion and exclusion criteria.

Recruitment will take place at the University Medical Center Groningen (UMCG), the Helen Dowling Institute (HDI), and through self-referral. At the UMCG, patients will be invited to the study by their oncologist or nurse, either at a follow-up appointment or during a phone call. Couples who indicate interest will be contacted by the research assistant. At the HDI, the research assistant will contact patients who are on the waiting list to receive patient-centered eMBCT and have given permission to be contacted for research purposes. Recruitment through self-referral will be encouraged by social media posts, newspaper articles, the panel of Kanker.nl [33], and flyers to be distributed at psychosocial care centers for people affected by cancer (Dutch: IPSO centra). Interested couples will be directed to the project website [34], where they can register.

The research assistant will schedule a web-based call with all interested couples to further inform them about the study and screen their eligibility. During the screening process, reasons for ineligibility and decline of participation will be recorded in the recruitment log as they inform our secondary aim (ie, feasibility of trial procedures). Upon obtaining informed consent from the patient with cancer and their partner, the patient will receive a link through email to a survey to confirm fatigue- and cancer-related eligibility criteria.

Participants will complete questionnaires before starting the intervention (T0), 2 weeks after completing the intervention (T1), and 1 month after T1 (T2). Patients and their partners will also complete weekly diaries, starting 1 week before the intervention and ending 1 week after the intervention is completed. All questionnaires and diaries will be provided on the web through a secure, web-based application called REDCap (Research Electronic Data Capture) [35]. Patients and their partners will receive a link sent to their personal email and will be encouraged to respond independently from each other. In the event of nonresponse to the questionnaire, participants will receive a reminder email after 7 days and a second reminder after another 7 days of nonresponse. In case a diary assessment is missed, participants will receive a reminder the next day, and if 2 consecutive diaries have not been responded to, the assistant will call the participant to discuss possible problems. Therapists will also keep a therapist log to register data on intervention delivery, and the research assistant will keep a recruitment log to register data on recruitment and study adherence. A subsample of 5 patients with cancer and 5 partners (anticipated sample sizes), as well as all therapists providing the COMPANION intervention, will be invited to participate in separate focus groups. Patients and partners will be sampled purposefully (ie, based on high vs low levels of adherence or intervention satisfaction) and can be invited independently from each other.

The study is powered to test the potential efficacy of the couple intervention in reducing patient fatigue (ie, the second primary research aim). Patients’ baseline (T0) and postintervention (T1) scores on the Checklist Individual Strength, subscale Fatigue Severity (CIS-fatigue) will be analyzed with a 1-tailed matched pairs t test. G*Power analysis indicated that 27 patients are required to detect a medium effect (0.5) with an α of .05 and a power of 0.8 (1-tailed). We expect CIS-fatigue scores at T1 to be significantly lower than CIS-fatigue scores at T0. We will conduct a 1-sided test given the gain in power as compared to a 2-sided test and evidence that an increase in mean fatigue is unlikely to occur [31]. Based on the drop-out rate in our previous trial [31] and a recent review of the attrition rate in couple-based interventions for cancer [36], we assume a 20% drop-out rate. Hence, we will aim to include a total of 34 couples.

COMPANION is a couple intervention developed from an evidence-based patient-centered eMBCT that aims to change the patient’s behavioral and cognitive reactions to cancer-related stressors, including fatigue [31]. Like the patient-centered eMBCT, COMPANION is web-based and guided remotely by a trained therapist. However, COMPANION also involves the patient’s partner in the treatment. The intervention consists of 9 sessions, which take approximately 15 to 20 weeks to complete (ie, the intervals between sessions are flexible to accommodate holidays and other commitments). Patients will have access to a secure web-based platform where they will receive written information about a specific theme for each session. Partners will have access to these materials through the patient. Table 1 provides an overview of all 9 sessions. Participants will be provided with audio files to practice different mindfulness-based cognitive-behavioral exercises each session. Patients will document their experiences in their personal log and perform exercises for approximately 30 minutes, 6 days a week. The exercises comprise topics such as relaxation, eating with awareness, moving with awareness, 3-minute breathing exercises, or meditation. Apart from the video call consultations, communication with the therapist will be mostly asynchronous, meaning that the therapist reads the experiences in the logs and provides feedback once a week. Adaptations compared to the patient-centered version were based on the findings from the preceding needs assessment among patients, partners, and therapists (van Dongen et al, unpublished data, 2023). These adaptations mainly concerned: 3 video call consultations between patient, partner, and therapist; psychoeducation for the partner; additional exercises for patient and partner (to be performed together or independently); and an extra session focused on the couple’s mutual relationship and mindful communication about fatigue. Together with their therapist, couples can decide how and to what extent their partner will be involved.

Therapists at the HDI will deliver COMPANION. They all fulfill the criteria established by the United Kingdom Mindfulness-Based Teacher Therapist Network Good Practice Guidelines for teaching mindfulness-based interventions [37]. They will be trained in providing the couple intervention by an experienced therapist and a researcher from the COMPANION project team. This training starts with a preparatory self-study assignment using the web-based COMPANION treatment environment (a web portal for therapists). Next, therapists participate in an interactive training session addressing the content of the new therapy, the role of the therapist within this new therapy (including exercises and suggestions for involving the partner and giving therapeutic feedback [38]), and the design and procedures of the COMPANION pilot trial. All information is documented in a detailed written manual for therapists. Regular supervision will take place during the pilot trial, led by a member of the COMPANION project team who is a registered supervisor at the Dutch Society for Cognitive Behavioral Therapy. This supervisor has 15 years of experience in psycho-oncology, including 12 years of work experience with the patient-centered eMBCT for CCRF.

Table 2 provides an overview of all the constructs to be assessed. For conciseness, we have only described the key measures. Where possible, we chose validated and widely used instruments in the field. Table 2 provides references for measures not described here.

Demographic characteristics will be assessed at the screening and T0 and include self-reported age, sex, level of education, occupational status, relationship status and duration, cohabitation status and duration, and comorbidities.

Patients’ cancer-related variables are self-reported and include cancer type, prognosis, presence of metastasis, treatment received, time since diagnosis, and time since treatment completion.

Intervention adherence will be assessed at T1, as self-reported by the patients and as registered by the therapists in their therapy log. The item used reads: “Did you/your client complete all sessions of the COMPANION therapy?” Answer categories are (1) “Yes, I/my client completed all sessions of the intervention” and (2) “No, I/my client stopped after session ____ (fill in the blank).” Reasons for stopping can be recorded in a free text field. By design, partners’ involvement in the intervention is flexible, as this was an important requirement derived from the preceding needs assessment study (van Dongen et al, unpublished data, 2023). We consider receiving 6 sessions to be the minimal therapeutic dose. Therefore, intervention completion is achieved when a patient receives ≥6 out of 9 sessions, as reported by the patient at T1 and/or in the postintervention therapist log, and the partner did not drop out from the intervention.

Intervention satisfaction will be assessed with items based on those of other pilot trials for patients and their loved ones [39,40]. For both patients and partners, a total of 2 items will be used to assess satisfaction with the intervention overall (ie, “Overall, how satisfied are you with the COMPANION therapy?”) and satisfaction with the couple approach (ie, “How satisfied are you with the possibility of jointly participating in the COMPANION therapy?”). Additional items assess satisfaction with specific aspects of the intervention. Items are scored on a 7-point Likert scale; scores 5 to 7 represent (high) satisfaction.

Fatigue severity will be assessed using the CIS-fatigue. A total of 8 items assess fatigue severity during the past 2 weeks (eg, “I feel tired”) and are scored on a 7-point Likert scale, ranging from (score 1) “Yes, that is true” to (score 7) “No, that is not true.” A higher sum score indicates more severe fatigue (range 8-56), with a score of ≥35 indicating severe fatigue in patients with cancer [42,43]. A clinically relevant change is operationalized as a difference of 6 points [52].

Recruitment rates: the research assistant will complete a recruitment log. The following information will be collected: (1) number of patients approached for recruitment (through the UMCG and HDI); (2) number of participants (ie, patient and/or their partner) interested in participation; (3) number of included couples; and (4) number of couples dropping out from the intervention and study. Along with these rates, reasons will be recorded. The recruitment rate is defined as the average number of couples included per month.

Adherence to the study protocol will be recorded by the research assistant in the recruitment log in terms of the number and percentage of questionnaires completed. Completion is defined as having responded at least to the items assessing the outcome measures.

Potential mechanism variables will be assessed in the weekly diary and include affect, sleep, catastrophizing, partner communication, partner interactions, self-efficacy, mindfulness, and closeness. Items are based on and adapted from a daily diary study among survivors of cancer and their partners [20,21,53] and existing scales. Table 3 provides an overview of the items.

Weekly fatigue severity in patients will be assessed with the 4-item Short Fatigue Questionnaire (SFQ) [54], a shortened version of the CIS-fatigue. The time frame has been adapted from the original past 2 weeks to the previous week, and items are formulated in the past tense (eg, “I felt tired”).

Current fatigue severity will be assessed in the weekly diaries with 1 item, “How fatigued do you feel right now?” that is scored on an 11-point Likert scale ranging from (score 0) “not at all” to (score 10) “as fatigued as I could be” [20,21,53].

Analyses will be conducted in SPSS (IBM Corp) and Mplus (Muthén & Muthén).

This study is subject to on-site monitoring based on the risk classification “negligible.”

This study has been approved by the medical ethics committee of the University Medical Center Groningen (registration number 2022/203, NL80201.042.22). The study is registered on ClinicalTrials.gov (NCT05636696). Written informed consent will be obtained from all participating patients with cancer and partners. A separate consent form will be signed by those who participate in the focus groups.