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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.
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.
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
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 (
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.
ISRCTN Registry 36621459; https://www.isrctn.com/ISRCTN36621459
Physiological and psychological changes following cancer diagnosis and its treatment may have detrimental effects on reproductive health [
Psychosocial interventions for cancer survivors, which may or may not include web-based components, often have a broad scope [
In the past decade, eHealth has exploded as a research and clinical discipline, and the number of psychosocial and psychological interventions has increased. Several reviews have pointed out the complex nature of eHealth interventions and the challenges involved in their testing and implementation [
It has been suggested that to be effective, complex eHealth interventions need to be underpinned by an explicit theoretical framework reflected in the proposed behavior change methods [
The intervention went through feasibility testing [
The aim of this study is to test the efficacy of the Fex-Can intervention in reducing fertility-related distress and psychosocial outcomes in young adults with cancer.
The specific research questions are as follows:
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?
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 with standard care?
Do baseline levels of fertility distress predict the effect of the program over time?
Does dose, that is, the uptake and adherence to the program, influence the change in fertility distress ratings over time?
The Fex-Can project encompasses a national cohort study [
The sample was drawn from a cohort of 1499 individuals diagnosed with breast, cervical, ovarian, or testicular cancer; lymphoma; or central nervous system tumor between 2016 and 2017, approximately 1.5 years before the start of the study. The time frame was chosen to approach people who were likely to have finished primary treatment but were 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 years 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 either on paper or via the web and included written informed consent. 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.
Respondents scoring ≥4 on at least 1 subscale of the Reproductive Concerns After Cancer (RCAC) scale [
Allocation (1:1 ratio) to either the intervention group (IG) or control group (CG) was performed by an external statistician uninvolved in the data collection process by stratified block randomization, taking into account sex and diagnosis. Owing to the design of the intervention, a placebo condition was not possible and neither participants nor researchers could be blinded to the group allocation. Participants were considered lost to follow-up only if they, for any reason, did not return the postintervention questionnaires; therefore, no pattern of attrition was determined after randomization. The flow of participants is summarized in
The sample size was estimated to be 128 individuals needed at follow-up, to obtain statistically significant results, assuming 80% power, medium effect size (ES; 0.5), and a significance level set at .05. As the attrition rate between baseline and first follow-up was expected to be around 15%, we aimed to include 210 participants at baseline.
Flow of participants—CONSORT SPI-2018 (Consolidated Standards of Reporting Trials Statement for Social and Psychological Interventions) flow diagram.
The intervention was a 12-week, web-based psychoeducational program. The Fex-Can Fertility program was organized in 6 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 [
The control condition was standard care, which may or may not have included fertility-related support and scheduled contacts with health care, depending on the diagnosis and treatment.
Participants were assessed on outcome measures and sociodemographic variables via a self-administered survey on the following three occasions: baseline (T0), directly after the intervention (T1), and 3 months later (T2). In addition, treatment intensity according to an adapted version of the intensity treatment rating scale [
The RCAC scale was developed for women in the United States with various cancer diagnoses [
Health-related quality of life was measured using the validated [
The Hospital Anxiety and Depression Scale is a widely used scale measuring anxiety (7 items) and depression (7 items), validated for use in patients with cancer [
Perceived confidence in one’s ability to manage situations and emotions related to the threat of infertility was measured using a study-specific questionnaire based on previous research [
The perceived level of knowledge concerning fertility issues was measured using a study-specific questionnaire developed from previous research [
At T1, participants who had been randomized to the IG were presented study-specific items concerning their experience of the program. Specifically, they were asked to rate their own perceptions of how their problems regarding having children after cancer had changed compared with before participating in the program. Answers were given on a 7-point Likert scale (
Data were analyzed using descriptive and inferential statistics. Statistical analyses were performed by external statisticians on blinded data. Missing data were treated as follows: for single items that were missing, we imputed according to the individual’s mean on the scale, provided half or more of the items had been answered. We chose not to impute for individuals where the entire scale was lacking (1-3 participants per group).
Linear mixed models were then used to analyze possible changes over time within and among the treatment groups on the main outcome measure. Mixed models consider the potential dependence of repeated observations within participants and compensate for missing data without the need for imputation [
This study was approved by the Regional Board of Ethics in Stockholm (permit numbers: 2013/1746-31/4, 2014/224-32, and 2017/916-32) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Eligible participants were persons aged 19 to 40 years, approximately 1.5 years after diagnosis with selected cancer types and reporting elevated levels of fertility distress in a population-based survey. Of the 433 eligible participants approached, 124 (28.6%) agreed to participate. The final sample consisted of 124 individuals, 24 (19.4%) men and 100 (80.6%) women. One participant was assessed at baseline but was excluded from follow-up due to technical failure. Participant characteristics, including sociodemographic and clinical variables, are summarized in
Randomization resulted in 64 patients in the IG and 60 in the CG. The attrition was lower than anticipated in the power calculation. At follow-up, of 124 participants, there were 108 (87.1%) and 101 (81.5%) responses from the IG and CG at T1 and T2, respectively (
At baseline, there were no statistically significant differences between the IG and CG in background variables or outcome measures. Breast cancer was the most common diagnosis among participants. Most of the participants had a partner, were working as their main occupation, and had a university or college level of education. Approximately half (29/64, 45% in the IG and 35/60, 58% in the CG) of the participants already had biological children. More than half of the participants (66/124, 53.2%) had received treatments that were very or most intensive or extensive.
Demographic and clinical characteristics recorded at the baseline assessment (T0; N=124).
Characteristics | Intervention group (n=64) | Control group (n=60) | |
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Men | 13 (20) | 11 (18) |
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Women | 51 (80) | 49 (82) |
Age (years), median (range) | 33 (20-41) | 34 (19-40) | |
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Sweden | 54 (84) | 51 (85) |
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Another European country | 3 (5) | 6 (10) |
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Outside Europe | 7 (11) | 3 (5) |
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University | 39 (61) | 34 (57) |
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High school | 20 (31) | 19 (32) |
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Secondary school or other | 5 (8) | 7 (12) |
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Working full-time or part-time | 42 (66) | 44 (73) |
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Student | 4 (6) | 4 (7) |
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On sick leave | 17 (27) | 11 (18) |
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Other (eg, unemployed or full parental leave) | 1 (2) | 1 (2) |
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Breast cancer | 26 (41) | 26 (43) |
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Brain tumor | 8 (13) | 6 (10) |
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Cervical cancer | 10 (16) | 12 (20) |
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Lymphoma | 11 (17) | 8 (13) |
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Ovarian cancer | 3 (5) | 2 (3) |
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Testicular cancer | 6 (9) | 6 (10) |
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None | 40 (63) | 39 (65) |
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Chemotherapy | 3 (5) | 2 (3) |
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Radiation | 1 (2) | 2 (3) |
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Hormonal treatment | 19 (30) | 17 (28) |
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Other (eg, antibodies) | 6 (9) | 4 (7) |
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Level 1: least intensive or extensive treatment | 10 (16) | 11 (19) |
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Level 2: moderately intensive or extensive | 20 (33) | 13 (22) |
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Level 3: very intensive or extensive | 29 (4) | 33 (56) |
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Level 4: most intensive or extensive | 2 (3) | 2 (3) |
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Partnered | 50 (78) | 52 (88) |
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Nonpartnered | 14 (22) | 7 (12) |
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Live with children | 30 (47) | 38 (63) |
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Had biological children before onset of cancer | 29 (45) | 35 (58) |
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Became a parent after cancer | 3 (5) | 2 (3) |
aAccording to the adapted version of the intensity treatment rating scale.
Of the 64 participants who were randomized to the IG, 21 (33%) reached the level of use defined as
Linear mixed models using a random intercept and based on intention to treat were conducted to study the effects of time and group on the evolution of the main outcome measure. The results are presented in
In intention-to-treat analyses,
Including RCAC baseline scores and activity in the program did not substantially change the results and did not produce any clear pattern (data available in
Difference in mean values between groups over time (linear mixed models with random intercept: group and time interaction; intention-to-treat: intervention group [IG] vs control group [CG]).
Outcome measure (RCACa; range 1-5) and group | T0 (baseline) | T1 (directly after the intervention) | T2 (3 months later) | ||||||||||||||||||
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Value, mean | Value, mean (95% CI) | Effect size (Cohen |
Value, mean (95% CI) | Effect size (Cohen |
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.30 | 0.20 |
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.22 | 0.24 | ||||||||||||||||
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IG | 3.33 | 3.17 (3.01-3.32) |
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3.07 (2.90-3.23) |
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CG | 3.29 | 3.28 (3.13-3.43) |
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3.20 (3.05-3.36) |
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.19 | 0.25 |
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.26 | 0.22 | ||||||||||||||||
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IG | 3.83 | 3.50 (3.21-3.78) |
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3.40 (3.11-3.69) |
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CG | 3.95 | 3.76 (3.48-4.04) |
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3.63 (3.35-3.92) |
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.42 | −0.15 |
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.38 | −0.17 | ||||||||||||||||
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IG | 3.24 | 3.15 (2.87-3.44) |
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2.99 (2.69-3.29) |
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CG | 2.95 | 2.99 (2.71-3.27) |
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2.80 (2.51-3.09) |
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.11 | 0.30 |
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.003 | 0.576 | ||||||||||||||||
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IG | 3.25 | 3.17 (2.86-3.47) |
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2.91 (2.60-3.22) |
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CG | 3.49 | 3.52 (3.22-3.82) |
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3.59 (3.28-3.90) |
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.46 | 0.14 |
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.74 | 0.06 | ||||||||||||||||
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IG | 3.30 | 3.25 (2.99-3.50) |
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3.22 (2.96-3.49) |
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CG | 3.36 | 3.38 (3.13-3.64) |
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3.29 (3.03-3.55) |
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.64 | −0.09 |
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.75 | −0.06 | ||||||||||||||||
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IG | 3.12 | 2.98 (2.66-3.31) |
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2.86 (2.53-3.19) |
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CG | 2.88 | 2.87 (2.55-3.20) |
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2.79 (2.45-3.12) |
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.46 | 0.14 |
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.61 | 0.10 | ||||||||||||||||
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IG | 3.25 | 3.02 (2.80-3.25) |
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3.10 (2.86-3.34) |
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CG | 3.10 | 3.14 (2.93-3.36) |
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3.18 (2.96-3.41) |
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aRCAC: Reproductive Concerns After Cancer.
Group differences in dimension 3 (child’s health). RCAC: Reproductive Concerns After Cancer.
There was a significant difference between IG and CG on the secondary outcome cancer-related fertility knowledge, where participants in the IG had better self-rated knowledge than controls at both follow-up points (T1: mean score 2.81 vs 2.54;
Mean group difference on secondary outcome measures at baseline, after the intervention, and 3 months after the intervention (N=124).
Outcome subscale (range) | T0 (baseline) | T1 (12 weeks; directly after the intervention) | T2 (24 weeks; 3-month follow-up) | ||||||||||
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IGa (n=64), mean (SD) | CGb (n=60), mean (SD) | IG (n=50), mean (SD) | CG (n=58), mean (SD) | Effect sized | IG (n=48), mean (SD) | CG (n=53), mean (SD) | Effect sized | |||||
HADSe anxiety (0-21) | 9.84 (4.45) | 8.58 (4.40) | 8.67 (4.59) | 8.40 (4.46) | .76 | 0.06 | 8.71 (3.77) | 7.73 (4.58) | .24 | 0.22 | |||
HADS depression (0-21) | 5.35 (3.61) | 4.76 (4.01) | 5.61 (3.85) | 4.36 (3.62) | .09 | 0.33 | 5.24 (3.87) | 3.96 (4.05) | .11 | 0.33 | |||
EORTC-QLQ-C30f sum score (0-100) | 73.34 (16.80) | 76.08 (18.58) | 75.06 (17.00) | 77.35 (19.40) | .52 | 0.13 | 78.01 (16.28) | 79.59 (18.15) | .65 | 0.09 | |||
Fertility self-efficacy (1-4) | 3.09 (0.75) | 3.30 (0.64) | 3.21 (0.66) | 3.20 (0.66) | .95 | 0.01 | 3.13 (0.78) | 3.31 (0.67) | .24 | 0.26 | |||
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General (1-4) | 3.58 (0.55) | 3.50 (0.74) | 3.51 (0.68) | 3.49 (0.75) | .87 | 0.03 | 3.55 (0.57) | 3.50 (0.59) | .69 | 0.07 | ||
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Cancer related (1-4) | 2.65 (0.82) | 2.60 (0.73) | 2.81 (0.70) | 2.54 (0.70) | .05 | 0.35 | 2.75 (0.76) | 2.38 (0,7) | .01 | 0.48 |
aIG: intervention group.
bCG: control group.
c
dCohen
eHADS: Hospital Anxiety and Depression Scale.
fEORTC-QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
At the postintervention evaluation (T1), participants in the IG completed a single item on self-perceived change in problems regarding fertility after cancer. Most of those who completed T1 (31/50, 62%) thought their problems had been alleviated: 30% (15/50 participants) improved a little, 22% (11/50 participants) improved, and 10% (5/50 participants) improved a lot. Of the 50 participants, 18 (36%) felt that their problems had not changed and 1 (2%) experienced a worsening situation and commented that this was not because of the program.
This study invited young adults with cancer who had reported fertility distress in a population-based survey to test the efficacy of a psychoeducational intervention, the Fex-Can Fertility program. This study aimed to determine the capacity of this web-based, self-help program in alleviating fertility distress as measured using the RCAC scale. Assessment at the 3-month follow-up after the end of the program showed significant differences in one out of six dimensions of the RCAC scale, child’s health, where the IG had less distress than the CG. Regarding the secondary outcome of cancer-related fertility knowledge, the IG reported better knowledge than the CG at both the directly postintervention and at the 3-month follow-up. ESs were small to moderate, with a more pronounced effect at the 3-month follow-up. Subgroup analyses assessing the possible interaction effect of time and group, adherence, and baseline RCAC scores on the main outcome measure did not substantially alter the results.
The results indicating a moderate effect on distress related to genetic risks for offspring and knowledge about fertility after cancer were expected, in the sense that the program contained clear information on these topics. Previous research has found that patients value reliable information and honest communication in health care [
The concept of adherence to eHealth interventions is contested because of a lack of agreement on whether reported measures really refer to use leading to intended effects or simply to use of any kind [
This study had very small formal dropout rates in the postintervention follow-up, that is, most participants returned questionnaires at both follow-up points. In an intention-to-treat manner, surveys were sent via mail to all patients who were randomized, regardless of their activity level. This means that participants who had not been very active in the program and some who had not even logged on to the website responded to postintervention surveys and were counted as completers alongside their more dedicated counterparts, possibly
Strengths of this study included having a thoroughly prepared, theory-based intervention designed with a participatory approach [
RCTs are usually considered the gold standard for scientific evidence. However, in social and psychological interventions, especially eHealth interventions, conditions are not fully controlled, as double-blinding is not possible. The researchers cannot influence what type of accessory support either the IG or the CG has access to, and substantial self-help information is readily available on websites via social or traditional media. This may lead to an inconclusive assessment of intervention effects. Furthermore, there are various sources of bias introduced by design choices, such as not having a set standard for adherence; for example, homework or a minimum assignment for participants. Although evidence for efficacious web-based psychoeducational interventions remains weak [
To the best of our knowledge, dimensions of the RCAC scale have been used as intervention outcome measures in only one previously published study. A study by Su et al [
This web-based psychoeducational intervention for young adults diagnosed with cancer had little overall effect on fertility-related distress. Small to moderate effects could be seen on cancer-related fertility knowledge and the level of concern for future children’s health. Further research on the mechanisms of impact is required to determine for whom the Fex-Can program or similar interventions may constitute an appropriate individualized support.
The Fex-Can Fertility program could be useful for improving knowledge about fertility and reducing concerns about genetic risks following cancer. The automated, flexible, and partially tailored design of the intervention makes it a convenient tool in clinical care. It appears safe to use because no adverse effects were reported and most participants reported subjective improvement in their concerns.
Study-specific instruments.
Significant differences in subgroup analyses based on activity level.
Subgroup analyses based on baseline levels of fertility distress.
Subgroup analyses based on activity level.
Reproductive Concerns After Cancer dimension 5 (acceptance). Subgroup analyses according to baseline levels.
CONSORT eHEALTH Checklist (V 1.6.1).
control group
Consolidated Standards of Reporting Trials
effect size
Fertility and Sexuality following Cancer
internet-based cognitive behavioral therapy
intervention group
Reproductive Concerns After Cancer
randomized controlled trial
self-determination theory
The authors would like to thank all the participants of the Fex-Can (Fertility and Sexuality following Cancer) intervention and the funders.
The software application code and the original data set are available upon reasonable request.
None declared.