Efficacy of a Web-Based Psychoeducational Intervention for Young Adults With Fertility-Related Distress Following Cancer (Fex-Can): Randomized Controlled Trial

Background Threatened fertility following cancer diagnosis in the reproductive age may severely impact emotional and psychosocial well-being in survivorship. Effective web-based interventions for fertility-related distress have been lacking. Objective This study aims to test whether the Fertility and Sexuality following Cancer (Fex-Can) intervention is superior to standard care in reducing fertility-related distress and related psychosocial outcomes in young adults with cancer. Methods This randomized controlled trial evaluated a 12-week, web-based, automated self-help intervention for fertility-related distress following cancer—Fex-Can Fertility. Individuals were identified via Swedish national quality registries, and those reporting fertility-related distress 1.5 years after diagnosis were invited. A total of 100 women and 24 men (aged 19-40 years) answered self-administered surveys at baseline (T0), directly after the intervention (T1), and 3 months later (T2). The main outcome was fertility-related distress, which was measured by using the 6-dimension Reproductive Concerns After Cancer (RCAC) scale. The secondary outcomes were health-related quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire), emotional distress (Hospital Anxiety and Depression Scale), fertility-related knowledge, and fertility self-efficacy. In addition, the intervention group (IG) reported self-perceived changes in problems related to fertility after cancer (T1). 2-tailed t tests and linear mixed models, including intention-to-treat and subgroup analyses, were performed to compare the effects of the intervention with those of standard care. Results Although 62% (31/50) of the participants in the IG stated that their concerns about fertility were fewer after the intervention, there were few statistically significant group differences in the main outcome (RCAC) at T1 and T2. Compared with controls, the IG rated lower distress concerning the dimension child’s health at T2 (P=.003; effect size [ES]=0.64). This difference was maintained when adding group and time interactions (intention-to-treat: P=.003; ES=0.58). The IG also had better self-perceived cancer-related fertility knowledge at T1 (P=.05; ES=0.35) and T2 (P=.01; ES=0.42) than the control group. Subgroup analyses based on dose or adherence and baseline RCAC scores did not substantially alter these results. Overall, the use of the web-based program was low. Conclusions The Fex-Can intervention had small to moderate positive effects on cancer-related fertility knowledge and distress related to child’s health. The lack of group differences in other dimensions of fertility distress and related secondary outcomes contrasted with reports on self-perceived improvement after the intervention. The Fex-Can Fertility program may be a useful complement to routine psychosocial support in the clinical care of young women and men with cancer. Trial Registration ISRCTN Registry 36621459; https://www.isrctn.com/ISRCTN36621459

INTRODUCTION 2a-i) Problem and the type of system/solution "Psychosocial interventions for cancer survivors, which may or may not include web-based components, often have a broad scope [13], and are referred to as 'survivorship care plans ' [14], self-management interventions [15] or multidimensional programs [16,17]. There is a shortage of interventions targeting both medical and psychosocial concerns about fertility and parenthood following cancer." 2a-ii) Scientific background, rationale: What is known about the (type of) system "In the past decade, eHealth has exploded as a research and clinical discipline, and the number of psychosocial and psychological interventions has risen. A number of reviews have pointed out the complex nature of eHealth interventions as well as challenges involved in their testing and implementation [19][20][21]. For example, there is limited evidence concerning dose and adherence measures [22]" Does your paper address CONSORT subitem 2b?
"The aim of the present study was to test the efficacy of the Fex-Can intervention in reducing fertility-related distress and related psychosocial outcomes in young adults with cancer. Specific research questions: 1)Is the Fex-Can Fertility program superior to standard care in reducing fertility distress directly after the end of the program, and 3 months later, respectively? 2)Does the Fex-Can Fertility program increase fertility self-efficacy and fertility-related knowledge, reduce emotional distress or improve health-related quality of life, compared to standard care? 3)Do baseline levels of fertility distress predict the effect of the program over time? 4)Does dose, i.e., the uptake and adherence to the program, influence the change over time in fertility distress ratings?"

3a) CONSORT: Description of trial design (such as parallel, factorial) including allocation ratio
The Fex-Can project encompasses a national cohort study [38] with an embedded randomized controlled trial (RCT) including participants with self-reported distress/dysfunction at baseline [39]. The Fex-Can web-based psychoeducational program was offered in two versions; Fex-Can Sex and Fex-Can Fertility, the latter being evaluated in the present study. Detailed description of the study design is available in two published study protocols [38,39] and is briefly described below. Allocation (1-1 ratio) to either intervention (IG) or control group (CG) was performed by an external statistician uninvolved in the data collection process, by stratified block randomization taking account of sex and diagnosis. Due to the design of the intervention a placebo condition was not possible and neither participants nor researchers could be blinded to group allocation. Participants were considered lost to follow-up only if they for any reason did not return post-intervention questionnaires; hence no pattern of attrition was determined post-randomization" 3b) CONSORT: Important changes to methods after trial commencement (such as eligibility criteria), with reasons There was a change in the number of primary outcome measures due to recent publications validating the use of the RCAC scale as six separate subscales rather than one mean score. 3b-i) Bug fixes, Downtimes, Content Changes Not relevant since it did not happen 4a) CONSORT: Eligibility criteria for participants "The sample was drawn from a cohort of 1499 individuals diagnosed with breast, cervical, ovarian or testicular cancer, lymphoma, or CNS tumor between 2016-2017, approximately 1.5 years prior to the start of the study. The time frame was chosen to approach people who were likely to have finished primary treatment but still close enough to diagnosis to be in need of psychosocial support. Eligible participants were identified using Swedish national quality registries and all people in the intended age bracket (18-39 at diagnosis) were approached for a longitudinal cohort study. Individuals reporting fertility distress at the baseline assessment were invited to the Fex-Can Fertility trial.

Eligibility
Respondents scoring ≥4 on at least one subscale of the Reproductive Concerns After Cancer (RCAC) scale [4] were eligible for the RCT."

4a-i) Computer / Internet literacy
Not relevant -we assumed only people with a certain level of cimputer literacy would consent to participate in a fully web-based intervention study. In addition, the target group were young adults in one of the most computerized countries in the world.

4a-ii) Open vs. closed, web-based vs. face-to-face assessments:
"Eligible participants were identified using Swedish national quality registries and all people in the intended age bracket (18-39 at diagnosis) were approached for a longitudinal cohort study with a letter containing a survey sent to their population registration address. The survey could be completed on paper or online." 4a-iii) Information giving during recruitment "Individuals reporting fertility distress at the baseline assessment were invited to the Fex-Can Fertility trial and had to send a signed form back granting their consent to participate in the RCT." 4b) CONSORT: Settings and locations where the data were collected Not applicable, data were collected all over Sweden. 4b-i) Report if outcomes were (self-)assessed through online questionnaires "The survey could be completed on paper or online" 4b-ii) Report how institutional affiliations are displayed 5) CONSORT: Describe the interventions for each group with sufficient details to allow replication, including how and when they were actually administered 5-i) Mention names, credential, affiliations of the developers, sponsors, and owners 5-ii) Describe the history/development process "The development, design, contents and structure of the intervention have been described in detail in previous publications [31, 37, 44]"

5-iii) Revisions and updating
Not applicable since no revisions were made during the trial 5-iv) Quality assurance methods The contents of the intervention went through expert review, which is described in previous publications 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used The source code will be provided upon reasonable request.

5-vii) Access
"The development, design, contents and structure of the intervention have been described in detail in previous publications [31,37,44]. "

5-viii) Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework
Intervention "The intervention was a 12-week, web-based psycho-educational program. The Fex-Can Fertility program was organized in six successive modules with informational material, texts and exercises aiming at developing competence and facilitating behavior change through a sound balance between change and acceptance strategies. The modules covered known aspects of fertility distress [4] and were entitled: Fertility after cancer, Handling anxiety, Trying to have children after cancer, My own health and my child's health, Not being able to have biological children, and Relationships. Contents are described in detail in a doctoral thesis aiming for a process and outcome evaluation of the Fex-Can Fertility intervention [44]. The mode of delivery was conceived to facilitate satisfaction of participants' basic needs according to self-determination theory [33]. It was assumed such theoretical orientation would enhance positive health outcomes such as self-efficacy and health-related quality of life [29]. Nuanced information and reliable facts were intended to leverage participants' competence. Written and filmed survivor stories as well as interactive quizzes and a discussion forum were included with the goal of helping participants find strategies to handle their concerns surrounding fertility and family-building after cancer by strengthening autonomy and relatedness. The development, design, contents and structure of the intervention have been described in detail in previous publications [31,37,44]. The discussion forum was moderated by one of the research partners [31] and by a member of the research team with clinical expertise in psychology or nursing. Adherence was defined using quantitative activity parameters retrieved from the website system data."

5-ix) Describe use parameters
"High activity was defined as: having opened at least half of the modules and spent a total of at least 20 minutes on the website (general activity), plus one of the following: having spent three minutes or more in the discussion forum, written a post in the forum, or answering 50% or more of the quizzes (interactivity). All participants who did not reach these criteria were categorized as "low activity", which could also include not having logged on to the program at all." 5-x) Clarify the level of human involvement "The discussion forum was moderated by one of the research partners [31] and by a member of the research team with clinical expertise in psychology or nursing. "

5-xi) Report any prompts/reminders used
This is described in more detail in previous publications 5-xii) Describe any co-interventions (incl. training/support) Not applicable since there were no co-interventions 6a) CONSORT: Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed

"Main outcome measure -Fertility distress The Reproductive Concerns After Cancer Scale (RCAC) was developed for women in the US with various cancer diagnoses [4] and has been validated for women in China [47] and Sweden [48]
, and for men in the US [12]. The scale consists of a total score and six three-item dimensions related to fertility, pregnancy and parenthood after cancer: Fertility potential (concerns about one's ability to become a biological parent), Partner disclosure (concerns related to telling a partner about possibly impaired fertility), Child's health (concerns for a biological child's health in relation to the parent's previous cancer diagnosis and treatment, specifically genetic risks), Personal health (concerns related to fear of not being able to or living long enough to raise a child), Acceptance (the extent of reconciliation with not being fertile or not having biological children, and Becoming pregnant (concerns related to efforts involved in achieving a pregnancy). Answers are given on a five-point scale ranging from Strongly disagree (1) to Strongly agree (5), where higher scores indicate higher level of concerns. The mean of the total score as well as the mean scores for each of the six dimensions, as recommended in a validation study of the RCAC, [49] were used as primary outcomes for the Fex-Can Fertility trial.

Emotional distress
The Hospital Anxiety and Depression Scale (HADS) is a widely used scale measuring anxiety (7 items) and depression (7 items), validated for use in cancer patients [52]. Scores are given on a numbered Likert scale ranging from 0 through 3 and for each subscale a total score 0-21 (with higher values indicating more anxiety/depressive symptoms) is calculated.
Fertility self-efficacy Perceived confidence in one's ability to manage situations and emotions related to the threat of infertility was measured with a study-specific questionnaire based on previous research [53,54], including six items with statements such as: "I feel confident that I can tell other people I'm concerned about my reproductive ability". All the items are available in Supplementary file 1. Answers were given on a 4-point Likert scale with alternatives ranging from completely disagree (1) to agree completely (4). An exploratory factor analysis (data not shown) indicated that one of the items was poorly correlated with the others. A mean score was calculated from the five remaining items, with higher values indicating higher levels fertility-related self-efficacy.

Fertility-related knowledge
The perceived level of knowledge concerning fertility issues was measured using a study-specific questionnaire developed from previous research [18] and consisting of 10 items. Answers were given on a 4-point Likert scale with alternatives ranging from completely disagree (1) to agree completely (4). Exploratory factor analysis (data not shown) on the total cohort of eligible participants indicated it was suitable to divide the scale into two domains; one for general fertility-related knowledge (4 items) and one for cancer-related fertility knowledge (6 items). Items included statements such as: "I have good knowledge regarding the menstrual cycle and when a pregnancy can occur" (general fertility knowledge) and "I have good knowledge regarding the effect of cancer and cancer treatments on reproductive ability" (cancer-related fertility knowledge). All the items are available in Supplementary file 1. Means were calculated for each subscale, with higher mean scores indicating better perceived knowledge" 6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed 6a-ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored "High activity was defined as: having opened at least half of the modules and spent a total of at least 20 minutes on the website (general activity), plus one of the following: having spent three minutes or more in the discussion forum, written a post in the forum, or answering 50% or more of the quizzes (interactivity). All participants who did not reach these criteria were categorized as "low activity", which could also include not having logged on to the program at all." 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained This is described in detail in previous publications 6b) CONSORT: Any changes to trial outcomes after the trial commenced, with reasons Not applicable, data were collected all over Sweden. 7a) CONSORT: How sample size was determined 7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size "Sample size was estimated to 128 individuals needed at follow-up, to obtain statistically significant results, assuming 80% power, medium effect size (0.5) and a significance level set at 0.05. Since the attrition between baseline and first follow-up was expected to be around 15%, we aimed to include 210 participants at baseline." 7b) CONSORT: When applicable, explanation of any interim analyses and stopping guidelines "Main outcome measure -Fertility distress The Reproductive Concerns After Cancer Scale (RCAC) was developed for women in the US with various cancer diagnoses [4] and has been validated for women in China [47] and Sweden [48], and for men in the US [12]. The scale consists of a total score and six three-item dimensions related to fertility, pregnancy and parenthood after cancer: Fertility potential (concerns about one's ability to become a biological parent), Partner disclosure (concerns related to telling a partner about possibly impaired fertility), Child's health (concerns for a biological child's health in relation to the parent's previous cancer diagnosis and treatment, specifically genetic risks), Personal health (concerns related to fear of not being able to or living long enough to raise a child), Acceptance (the extent of reconciliation with not being fertile or not having biological children, and Becoming pregnant (concerns related to efforts involved in achieving a pregnancy). Answers are given on a five-point scale ranging from Strongly disagree (1) to Strongly agree (5), where higher scores indicate higher level of concerns. The mean of the total score as well as the mean scores for each of the six dimensions, as recommended in a validation study of the RCAC, [49] were used as primary outcomes for the Fex-Can Fertility trial.

Secondary outcome measures
Health-related quality of life Health-related quality of life was measured with the validated [50] summary score (range 0-100) of the EORTC-QLQ-C30 version 3.0 questionnaire which is a generic instrument for all cancer diagnoses [51].

Emotional distress
The Hospital Anxiety and Depression Scale (HADS) is a widely used scale measuring anxiety (7 items) and depression (7 items), validated for use in cancer patients [52]. Scores are given on a numbered Likert scale ranging from 0 through 3 and for each subscale a total score 0-21 (with higher values indicating more anxiety/depressive symptoms) is calculated.
Fertility self-efficacy Perceived confidence in one's ability to manage situations and emotions related to the threat of infertility was measured with a study-specific questionnaire based on previous research [53,54], including six items with statements such as: "I feel confident that I can tell other people I'm concerned about my reproductive ability". All the items are available in Supplementary file 1. Answers were given on a 4-point Likert scale with alternatives ranging from completely disagree (1) to agree completely (4). An exploratory factor analysis (data not shown) indicated that one of the items was poorly correlated with the others. A mean score was calculated from the five remaining items, with higher values indicating higher levels fertility-related self-efficacy.
Fertility-related knowledge The perceived level of knowledge concerning fertility issues was measured using a study-specific questionnaire developed from previous research [18] and consisting of 10 items. Answers were given on a 4-point Likert scale with alternatives ranging from completely disagree (1) to agree completely (4). Exploratory factor analysis (data not shown) on the total cohort of eligible participants indicated it was suitable to divide the scale into two domains; one for general fertility-related knowledge (4 items) and one for cancer-related fertility knowledge (6 items). Items included statements such as: "I have good knowledge regarding the menstrual cycle and when a pregnancy can occur" (general fertility knowledge) and "I have good knowledge regarding the effect of cancer and cancer treatments on reproductive ability" (cancer-related fertility knowledge). All the items are available in Supplementary file 1. Means were calculated for each subscale, with higher mean scores indicating better perceived knowledge"