Background
Cancer in adolescents and young adults (AYAs; ages 15–40 years) leaves unique health and social disruptions in patients and their families for many years of survivorship even after completing successful cancer therapy.1–4 As vital key providers for several levels of care and support, parents of AYAs with cancer are “the unsung heroes” in these trying situations.2 With the onset of illness and treatment, a shift toward greater dependence on parents and healthcare providers occurs, and the tendency for many parents to become overly protective may interfere with normal psychosocial AYA development.4–7 Parents reassume their earlier parental roles, almost independent of the actual age of a child who has become an AYA patient with cancer. On the one hand, parents’ role changes in caring for an adult child with cancer.3–8 On the other hand, parents provide complex care at home (eg, symptom management, treatment monitoring, ensuring adequate nutrition and physical activity), maintain their child’s financial autonomy, and are both navigators for a complex and fragmented healthcare system and faithful companions in cancer therapy.2–21 Remarkably, the renewed reappearance of coping strategies and conflicts between parents and their adult child after cancer diagnosis happens regardless of the child’s age.4–7,16–20 In one study, almost 42% of parents of AYA patients scored above a clinical cutoff score indicating posttraumatic stress symptoms, and nearly one-third reported moderate to severely elevated symptoms of anxiety and depression.16
In recent years, dramatic improvements in survival rates of patients with hematologic malignancies have been achieved through the introduction of molecular and personalized treatment approaches.22–27 Even so, AYAs with cancer have not, in general, attained the same improvements in overall survival as younger children or older adults.1 Currently, the care of AYAs with cancer under standard oncology care is seldom tailored to the specific needs of this particular patient population, tends to be incomplete and limited, and does not represent integrated medical care.4,5,9–16 There is a strong need for personalized AYA treatment and prevention approaches, and researchers and clinicians are just beginning to develop specific AYA health services.1,2,9–16 Recognizing and understanding AYA patients and their parents as primary caregivers as a functional coping dyad or an intertwined “psychological system” has essential clinical implications for effective cancer management, patient functioning, and cancer survivorship.4–20
AYA patients’ and parents’ beliefs about the illness’s severity may not be based on clinical indicators often used by healthcare professionals. Overall, most patients’ and caregivers’ illness perceptions are not associated with risk prognosis, healthcare utilization, or treatment-related expenses.20,28 As parents are experiencing high levels of distress, feelings of guilt, and personal accountability, maladaptive coping and numerous time-consuming demands may negatively affect their own physical and mental health, and this in turn may negatively affect the health outcomes of AYA patients.2–7,16–20,29,30 Parents’ self-reported concepts of cancer and treatment (such as a self-reported theory on the causal attribution) may sometimes lead to irrational or maladaptive coping with their child’s cancer situation.6,7,16–20,28 However, no randomized controlled trial (RCT) has evaluated a psycho-oncologic intervention program for parents of a child with cancer aged 18 to 40 years.2–21,31–34
We hypothesized that parents of AYAs with cancer who receive caregiver-centered special consultation in the setting of standard adult oncology care would have enhanced adaptive coping capabilities compared with parents who only receive standard care (SC). We evaluated changes in the rates of depressive symptoms and mental health as secondary clinical endpoints.
Patients and Methods
From November 30, 2012, to August 29, 2016, we enrolled mothers and fathers of AYAs with hematologic malignancies in a nonblinded, phase III RCT of the CSI AYA-Parents research-based coping support intervention (CSI group) compared with the SC group alone. The study was performed in accordance with the International Conference on Harmonization-Good Clinical Practice guidelines and preregistered on the German Clinical Trials Register (ID: DRKS0000425; UTN: U1111-1132-8011). The trial was planned and supervised based on process-oriented quality management (DIN ISO 9001) with the following implementations: process monitoring, data monitoring, data protection regulation, study protocol, failure management, accredited advanced training for oncologists and psychotherapists, and auditable standard operating procedures. The protocol, including the statistical analysis plan, was approved by the ethics committee of the Otto-von-Guericke University, Magdeburg, Germany. All authors guarantee the completeness and accuracy of the data and attest to the fidelity of the trial with the protocol.
Study Participants
Eligibility criteria included parents of a child with a clinical diagnosis of a hematologic malignancy (initial manifestation between ages 15 and 40 years) with acute care or follow-up care after cancer treatment; an ECOG performance status of 0, 1, or 235; study inclusion between ages 18 and 40 years; and ability to comprehend, read, and respond to questions in German. Patients in a palliative care setting or on strongly sedating substances were ineligible for participation in the study.
Screening and Randomization
The developmental needs of AYAs with cancer along with changes that their families specifically experience are often a unique challenge in recruitment into and adherence to a clinical trial.2–15,36–39 Our research strategy was elaborated according to so-called pragmatic clinical trials for patients with rare cancers and included as a key principle the maximization of the usefulness of the data gathered in the trial (eg, to prevent missing data; see supplemental eAppendix 1, pages 9–10, available with this article at JNCCN.org).36–40 Pragmatic trials can emulate real-world experiences in the application of study findings with an increased external validity (generalizability in the real world).40,41 For example, we implemented this approach through high-frequency and personal onsite communication, the creation of a research network (the German Study Group AYA Cancer Network), and the foundation of the first regional patient advocacy group for AYAs with cancer.
Study participants were recruited via the cancer care situation of their children with cancer. Research staff queried the electronic health record documentation to identify potentially eligible patients and obtained permission from oncologists to approach patients at their upcoming clinic visits. We performed 2-tier recruitment by ad hoc recruitment and systematic database queries to ensure homogeneous sampling (see supplemental eAppendix 1, pages 9–10). AYA patients were approached regardless of whether their parents were with them in the clinic. When parents were not present, AYA patients were asked to approach their parents to get in contact with the investigators. Parents who met prescreening criteria underwent an in-person evaluation and baseline assessment. Eligible participants were randomly assigned in a 1:1 ratio after enrollment using the minimization method of Pocock and Simon (randomization via Randomization in Treatment Arms [RITA] software, StatSol) as a highly effective allocation method42,43 with the stratification of parental emotional distress-coping (2 stages; measured using the Distress Thermometer, cutoff ≥4),44 treatment status (2 stages; present acute cancer treatment vs no treatment), and family situation (2 stages; single-parent vs 2-parent family). Outcome assessors were unaware of the group assignments.
Test Procedures
The Computer-Based Health Evaluation System (CHES)45,46 was applied using self-assessment questionnaires and 2 external assessments at 4 measurement dates: T0 (baseline), T1 (pretreatment), T2 (posttreatment), and T3 (follow-up, at most 3 months after T0).
Intervention
Successful coping strategies develop based not only on objective but also on self-reported evaluation mechanisms. Coping with illness is generally modulated by patients’ subjective theories of illness (STOI).6,7,16–20,28 STOI are defined as the cognitive constructions that people with illness make regarding (1) the nature of their disease, (2) its source, and (3) its treatment.28 We assumed that maladaptive coping results from maladaptive STOI. For example, there is excessive strain on a daughter (age 28 years, Hodgkin lymphoma) as an integral part of the mother’s STOI regarding the source of the daughter’s cancer. As a result, the mother behaves in an overprotective manner. The mother shows “love” with anxiety and fails to honor the daughter’s boundaries (physical, emotional, social, and psychological boundaries). Thus, she provokes both further serious conflicts with the young adult daughter striving for autonomy and further problems in the daughter’s cancer survivorship. For example, the daughter engages in emotional eating in response to these negative effects and conflicts, leading to grade 3 obesity.16–20,28,47,48
CSI AYA-Parents was a 5-session 1-on-1 therapy employing a supportive-psychodynamic approach.21,29–34,49 As in other supportive-psychodynamic treatments, the central elements were (1) the support of psycho-oncologic information processing, (2) the reflection and modification of the parents’ STOI and the individual coping strategies for dealing with cancer situation, and (3) the reflection and verbalization of role changes within the family system and changes in the relationship to the child with cancer (see supplemental eAppendix 1, pages 6–7).21,48 The primary therapeutic focus of the intervention was parental self-support. CSI AYA-Parents consisted of the following elements:
• Communication of objective information relevant to cancer and cancer treatment using information from recognized cancer counseling services. By using verified information, we achieved standardization of the basic information.
• Verbalization of self-reported illness concepts regarding the nature of the illness and nature of the treatment, self-reported attribution of causes and prognosis estimation, and cognitive-affective evaluation and modification.
• Development of individual (especially functional) aspects of coping with illness and clarification of approaches for the development of problem-oriented strategies.
• Considering the effects of the current illness situation on the parent–patient relationship from the point of view of the developmental psychosocial situation of the AYA patients and pointing out change options taking into account the emotional coping with the illness. The fifth treatment session was conducted together with the parents and their AYA patients in order to deeply assess changed relationship aspects and their effects on subjective regulation based on the cancer diagnosis.
Based on extensive preliminary work and given the research desiderata, CSI AYA-Parents was developed and clinically tested with parents of AYAs with hematologic malignancies between 2009 and 2011 within the outpatient supportive care clinic at the University Hospital of Magdeburg.28,31 The 5 sessions were offered once weekly. One treating psychotherapist was trained and supervised by 3 experienced psychotherapists/physicians. To assure treatment integrity, the treating psychotherapist presented each participant at 2 time points under individual supervision (after the first session with M. Koehler and before the fourth session with J. Frommer and H.H. Flechtner).
Parents of AYA patients randomly assigned to the SC group were not invited to a special counseling session unless a standard of care consultation was requested by the AYA patient, parent, or oncologist (“as usual”). However, this situation was never encountered in our clinical trial. All SC parent–child dyads continued to receive routine oncologic care throughout the study period without any special counseling.
Evaluation Strategy for the Primary Endpoint
As the primary outcome, we defined the change score using the adaptive coping (AC) scale of the 28-item Brief COPE instrument (change in AC score from T1 to T2), a validated multidimensional self-assessment questionnaire recommended for clinical cancer research that assesses 14 coping strategies using conceptually different subscales with 2 items per scale (internal consistency, α=0.68).50 Scores on the AC scale range from 4 to 32; higher scores indicate more frequent use of AC strategies. To achieve clinical validity and adequate reliability, the construction of the AC scale followed a research-based 3-step evaluation strategy (see supplemental eAppendix 1, page 4). The resultant AC scale used 8 items with 4 subscales (use of emotional support, active coping, use of instrumental support, and planning; Table 1).
Secondary Endpoints
Depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9; internal consistency, α=0.88) per the DSM-IV criteria.51,52 Validated for clinical cancer research, total severity scores according to the PHQ-9 range from 0 to 27, with a higher score indicating worse depressive symptoms. The PHQ-9, scored as a continuous measure, has performed well in identifying minor depressive disorder in patients and is considered a valid screening instrument (cutoff score of ≥5 in identifying minor depressive disorder).51,52 We defined the change of the PHQ-9 score from T1 to T2 as a secondary outcome.
Mental health was recorded using the 36-Item Short-Form Health Survey (SF-36),53,54 a compact, reliably developed, and well-tested instrument with an international standardized implementation (internal consistency, α=0.70). This 36-item instrument assesses 8 dimensions separated as summary scores in physical health and mental health (mental component score [MCS]), with higher total scores indicating better quality of life. Scores range from 0 to 100; higher scores indicate better mental health. We defined the change of the MCS score from T1 to T2 as a secondary outcome.
Parental emotional distress/coping was measured as a stratified variable with the use of the Distress Thermometer as a 1-item-scale (2 stages; cutoff ≥4).44 The Distress Thermometer is a compact, reliably developed, valid instrument for screening family members of patients with cancer for clinically significant distress in the form of symptoms of depression and anxiety (construct validity, r of 0.65–0.69; discriminative validity, area under the curve of 0.81–0.85). Participants were asked to rate how distressed they felt in the previous week on a single-item scale ranging from 0 (not distressed) to 10 (extremely distressed).
Statistical Analysis
The primary endpoint was the change score of the AC scale from T1 to T2. Secondary endpoints included an evaluation of the change of depression and mental health scores from pretreatment to posttreatment (T1 to T2), and the effect sizes. All analyses were performed on an intention-to-treat (ITT) basis. We followed the rules and checklist of the CONSORT statement and used the 4-point ITT analysis strategy for trials with incomplete outcome data according to White et al.55 Parents in the same household were considered as individual participants in the randomization. We had to maximize the recruitment by including mothers and fathers in the same household. This broadening of eligibility criteria had to be balanced against the possibility of dilution of the treatment effect.39 However, with this decision we achieved an increase in external validity (generalizability to the real world). If we had strictly focused on maximizing internal validity and ignored external validity, we would have had to focus strictly on recruiting mothers.40,41 Randomized participants were included in the ITT analyses, if T2 data assessment of these participants was completed disregarding intervention-related protocol deviations in the CSI group (90% of participants with 5 sessions). Due to CHES-based assessment,45 all questionnaire sets were completed (assessment completion rates of 100%). Because of the low proportion of withdrawal by parents or refusal to participate (<5%), we omitted these participants from the dataset (listwise deletion). We performed sensitivity analyses (eg, using methods based on multiple imputations or likelihood-based methods, including intrafamily correlation) to explore the impact of possible departures (parental sex, participants as a parent couple) from the assumptions made in the main ITT analysis. Concerning the outcome data, the statistical significance was tested at a significance level of .05 using 2-tailed independent t tests.
Baseline data were compared using Pearson chi-square tests or 2-tailed independent t tests. Effects of potential covariates were examined using univariate analyses of variance (ANOVAs). We calculated mean change scores in outcomes and estimated intervention effect sizes (Cohen’s d and dCorr as the corrected effect size per Klauer and Phye,56 considering baseline mean differences and differences in standard deviation, representing a more conservative method compared with Cohen’s d ),56 with 0.2 indicating a small effect, 0.5 a medium effect, and 0.8 a large effect.57 As additional measures of clinical benefit, we calculated the number needed to treat,58 the risk difference,57 and the binomial effect size display.57
With 146 participants, we estimated that the study would have 80% power at a one-tailed alpha level of 0.025 to detect a significant between-group difference in the change in AC score from pretreatment (T1) to posttreatment (T2) with an effect size of g=0.47.21 All data analyses were conducted using SPSS Statistics, version 24 (IBM Corp), and SAS 9.4 (SAS Institute Inc).
Results
Between November 30, 2012, and August 29, 2016, our study enrolled 106 families of AYAs with cancer and 182 parents; 29 parents declined to participate (Figure 1), resulting in a total of 153 parental caregivers recruited for assessment and randomization.
CONSORT flow diagram. Data assessment at T1 was completed by 152 parent–child dyads (dropout rate: 0.7%), at T2 by 146 parent–child dyads (4.6%), and at T3 by 142 parent–child dyads (7.2%). The dropout rate did not differ significantly between the study arms at either T1, T2, or T3 (see Table 3). Except for 1 mother, the parents of the intervention group attended ≥3 intervention sessions. Concerning our stratified variables and regardless of group assignment, dropout at T2 was associated with cancer treatment status (6 of 7 noncompleters were undergoing active cancer treatment; chi-square, P<.001) and distress level (all 7 noncompleters had a distress score >3; chi-square, P=.049).
Abbreviations: T0, baseline; T1, pretreatment; T2, posttreatment; T3, follow-up.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7075
Patient- and disease-related characteristics were distributed equally between the study groups (Tables 2 and 3). There were no significant differences in baseline demographic variables or the primary and secondary outcomes between participants who completed the trial and those who did not. Despite randomization, we found significant between-group differences indicating higher distress in the CSI group related to distress level. Of note, 53.5% of participants in the SC group and 75.6% of participants in the CSI group indicated high-level emotional distress as measured with the Distress Thermometer (Table 3).44 Two-factor ANOVAs did not reveal any main or interaction effect of the baseline distress level on each outcome measure. Thus, no further subgroup analyses were necessary.
Baseline Characteristics of the Participating Dyads
Pattern of Between-Group Differences of Baseline Characteristics in Dependence on Dropout
Primary Outcome
The comparison of the change score of the AC scale from T1 to T2 (Table 4, Figure 2A) showed that the parents assigned to CSI AYA-Parents had significantly increased scores than did those assigned to the SC group (P=.013; d=0.405). Using the corrected effect size dCorr per Klauer and Phye,56 we achieved a robust clinically significant improvement of AC in the CSI group (dCorr=0.345).
AC, Depression, and Mental Health as Assessed at T1 and T2 and Corresponding Change Scores
Evaluation of change scores between the 2 study arms from pretreatment to posttreatment (T1 to T2). We used the ratio of T2/T1 to illustrate the change. The change score represents the relative change between the pretreatment and the posttreatment value. A ratio of >0 means a symptomatic increase and a ratio <0 means a symptomatic decrease. Using the study group as the independent variable, 2-sided independent t tests showed significant between-group differences in the mean change of the (A) AC score (1.01 ± 4.2 in the CSI group vs –0.40 ± 2.6 in the SC group; difference between groups: 1.42; 95% CI, 0.30–2.54; P=.01; dCohen’s=0.405; dCorr=0.345) and the (B) PHQ-9 score (–0.70 ± 3.1 in the CSI group vs 0.44 ± 1.9 in the SC group; difference between groups: –1.14; 95% CI, –1.98 to –0.30; P=.008; dCohen’s=0.433; dCorr=0.419). A clinically significant change was observed between group differences in the (C) MCS score (1.19 ± 7.7 in the CSI group vs –0.70 ± 4.8 in the SC group; difference between groups: 1.89; 95% CI, –0.19 to 3.97; P=.07; dCohen’s=0.292; dCorr=0.194). Data derive from all parents who completed the T2 assessment (CSI group: n=77; SC group: n=69). Error bars indicate 95% confidence intervals.
Abbreviations: AC, adaptive coping; CSI, coping support intervention; MCS, mental component summary; PHQ-9, Patient Health Questionnaire-9; SC, standard care; SF-36, 36-Item Short-Form Health Survey; T1, pretreatment; T2, posttreatment.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7075
Participants in the CSI group had a clinically relevant AC improvement of 10.74% in contrast to the SC group, whose AC deteriorated (–0.61%). In other words, parents in the CSI group used statistically significant more instrumental support or emotional support compared with the SC group. The sensitivity analysis for exploring significant group differences of AC scores at T1 (pretreatment) revealed a significant influence of the T1 AC scores on the outcome scores at posttreatment; the effect of group assignment remained significantly detectable.
An analysis of clinical benefits (Table 5) revealed a significantly higher proportion of parents showing an AC increase in the CSI group compared with the SC group (P<.001), documenting a clinically significant improvement (d=0.698). Table 5 shows that using CSI AYA-Parents lowered the risk of maladaptive coping by 28% (binomial effect size display; Figure 3A). In other words, 28 out of 100 parents of an AYA with cancer were spared maladaptive coping if they were assigned to the CSI program.
Measures of Clinical Benefit
(A) Individual changes in the AC score from T1 to T2. For the pattern of distribution of the 3 outcome categories—“increase” (n=42 in CSI group vs n=18 in SC group), “unchanged” (n=10 in CSI group vs n=25 in SC group), and “decrease” (n=25 in CSI group vs n=26 in SC group)—we found a significant between-group difference using the chi-square test (P<.001). For further analysis, we used the ratio of T2/T1 to illustrate the change of the outcome values (see Table 5). (B) Individual changes in the PHQ-9 score from T1 to T2. For the pattern of distribution of the 3 outcome categories—“increase” (n=26 in CSI group vs n=29 in SC group), “unchanged” (n=15 in CSI group vs n=23 in SC group), and “decrease” (n=36 in CSI group vs n=17 in SC group), we found a significant between-group difference using the chi-square test (P=.02). For further analysis, we used the ratio of T2/T1 to illustrate the change of the outcome values (see Table 5).
Abbreviations: AC, adaptive coping; CSI, coping support intervention; PHQ-9, Patient Health Questionnaire-9; SC, standard care; T1, pretreatment; T2, posttreatment.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7075
The 4 sensitivity analyses for exploring the impact of possible departures from the assumption confirmed the robustness of the main ITT analysis (P≤.032; intraclass correlation coefficients ≥0.348; Table 6).
Sensitivity Analyses Confirmed the Robustness of the Main Intention-to-Treat Analysis
In addition, Figure 4 shows the secondary evaluation of the mean change scores between the 2 study arms from pretreatment to follow-up (T1–T3; T3 completers, n=142) with a clinically but not statistically significant AC improvement for the parents assigned to CSI AYA-Parents (dCorr=0.24). However, the follow-up analysis was less robust because of the expected loss of participants and therefore the loss of power.
Evaluation of the mean change in outcome scores between the 2 study arms from pretreatment to follow-up (T1 to T3). Using the study group as the independent variable, 2-sided independent t tests showed clinically significant but no statistically significant between-group differences in the mean change of the (A) AC score (0.47 ± 4.1 in the CSI group vs –0.45 ± 3.1 in the SC group; difference between groups: 0.91; 95% CI, –0.28 to 2.11; P=.13; dCohen’s=0.25; dCorr=0.24) and the (B) MCS score (–1.00 ± 7.5 in the CSI group vs 0.06 ± 6.1 in the SC group; difference between groups: 1.06; 95% CI, –1.22 to 3.33; P=.36; dCohen’s=0.15; dCorr=0.14). (C) The analysis of the depressive symptoms (PHQ-9 change score) from T1 to T3 showed that parents assigned to CSI AYA-Parents had significantly decreased scores compared with those assigned to SC, with an effect size in the small to medium range (–0.60 ± 2.8 in the CSI group vs 0.30 ± 2.3 in the SC group; difference between groups: –0.90; 95% CI, –1.78 to –0.04; P=.04; dCohen’s=0.35; dCorr=0.22). Data derive from all parents who completed the T3 assessment (CSI group: n=75; SC group: n=67). Error bars indicate 95% confidence intervals and standard error.
Abbreviations: AC, adaptive coping; AYA, adolescent/young adult patient; CSI, coping support intervention; MCS, mental component summary; PHQ-9, Patient Health Questionnaire-9; SC, standard care; T1, pretreatment; T3, follow-up.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7075
Secondary Outcomes
Depression
The evaluation of the depressive symptoms (PHQ-9 change score) from T1 to T2 (Table 4, Figure 2B) showed that the parents assigned to the CSI group had significantly decreased scores compared with those assigned to SC (P=.008; d=0.433). Analysis of clinical benefits indicated a significantly higher proportion of parents showing a depressive symptom decrease in the CSI group compared with the SC group (P=.006; Table 5), documenting a clinically significant improvement (d=0.517). Using CSI AYA-Parents, we achieved a clear reduction in the risk difference of the proportion of clinically relevant depression between the 2 study arms from pretreatment (30%) to posttreatment (13%; Table 5, Figure 3B).
Discussion
In this RCT, we found that a research-based CSI (CSI AYA-Parents) for parents of AYAs with hematologic malignancies was effective in enhancing parents’ AC and depressive symptoms. In addition, there was a trend toward improvement in mental health. In follow-up analyses, we found no significant between-group differences in effect, except for a significant improvement in depression in the intervention group compared with the control group (P=.04; dCohen’s=0.35; dCorr=0.22). However, the follow-up analyses were less reliable because of the expected loss of n and therefore the loss of power. Thus, further studies should be conducted that are powered to detect changes in longer-term follow-up. Although families of AYAs with cancer are confronted with high rates of mental and psychosocial concerns,16,18,20,23,59–61 the results of this trial indicate that they benefit from a supportive-psychodynamic and family-based approach in AYA oncology care.
Compared with other patient age groups and peer control groups, AYAs with cancer are highly vulnerable to long-term medical and psychosocial complications, are often more dependent on parents, and are more likely to fill antidepressant prescriptions.2–15,59–61 On the other hand, parents have significant potential to positively or negatively impact their child’s adjustment to daily demands and survivorship activities post cancer therapy.2–8,16–20,62 However, no clinical trial has shown the efficacy of a intervention program in reducing rates of depression and enhancing AC and mental health in this specific population. Thus, this study adds to the pediatric and adult cancer care literature by showing that a short-term psycho-oncologic intervention can effectively improve mental health in parents of AYAs with hematologic malignancies.
The CSI AYA-Parents protocol focused on a supportive-psychodynamic approach for changing problematic behaviors, feelings, and thoughts by disclosing parents’ (occasionally unconscious) meanings and motivations.49 We hypothesize that the 5 inherent treatment building blocks that constitute evidence-based practice led to enhanced AC and mental health parameters. However, the mechanisms behind the therapeutic change in participants’ subjective conceptions and coping skills (mind and behavior) remain less understood and necessitate future investigations. Along these lines, note that the treatment response observed was influenced by the recruitment of a highly affected study population. We found that 65.4% of parents of AYA patients (75.6% of participants in the CSI group vs 53.5% of participants in the SC group) reported Distress Thermometer scores within a clinically significant range. Two-factor ANOVAs did not reveal any main or interaction effect of the baseline distress level on each outcome measure. However, we believe that using the minimization method of Pocock and Simon is a very suitable configuration with regard to typical quality criteria and with regard to the high level of distress in the study population. Minimization as a highly effective allocation method is recommended for wider adoption in the conduct of RCTs.42,43
The construction of the AC scale followed a research-based 3-step evaluation strategy in our study. We achieved clinical validity and adequate reliability with the AC scale. However, the interpretation of an AC composite score is an area of debate. According to the current literature, a research-based calculation of composite subscales or a selection of coping strategies is a valid strategy.63–66
Our phase III RCT has a number of strengths: a 4-point AYA-Parents recruitment and data strategy according to recommendations for research methods to change clinical practice for patients with rare cancers (see supplemental eAppendix 1, pages 9–10)36–41; representative, homogeneous sampling with inclusion of mothers and fathers (with 36.6% fathers) for which we obtained a high agreement with family responsibility realities; <5% withdrawal rate of participants for the primary outcome analysis; and assessment completion rates of 100%. The study was planned and supervised based on standardized, process-oriented quality management (DIN ISO 9001) and was adequately powered to detect relevant changes in both AC and mental health. Compared with recruitment rates of approximately 10% in other cancer clinical trials in an AYA setting, the recruitment of 23% supports the credibility of the results obtained.36,37
However, we also acknowledge the limitations of this study. First, this RCT was conducted by a specialized team. This particular setting may limit the generalization of the results to other care settings or parents of AYAs with other types of cancer. Second, participants were aware of their randomized intervention assignment. This awareness may have initiated biases in the treatment courses and trial results. Third, parents in the same household were considered as individual participants in the randomization. We allowed both parents to be included based on practical recruitment considerations. The developmental needs of AYAs with cancer along with changes that families of AYAs with cancer specifically experience are often a unique challenge to recruitment into a clinical trial and adherence to the trial.2–15,36–39 Our research strategy was elaborated according to so-called pragmatic clinical trials for patients with rare cancers and included as a key principle the maximization of the usefulness of the data gathered in the trial. Despite their strengths, RCTs have substantial limitations. Although they can have strong internal validity, RCTs sometimes lack external validity (generalizability in the real world); generalizations of findings outside the study population may be invalid.40,41 So-called pragmatic trials require that participants are similar to patients who would receive the intervention if it became usual care, which may be unknown for new interventions.40,41 Notably, the number of parents in the same household was distributed equally between the study groups (20 pairs of parents in the CSI group, 19 pairs of parents in the SC group). In addition to these 39 pairs of parents who were randomized into the same study arm, 8 pairs of parents from one household were randomized into different study arms. If we had strictly focused on maximizing internal validity and ignored external validity, then recruiting and reaching the necessary sample size would have failed. Our efforts were intended to ensure transparency in study methods, provide standardized data collection for key outcomes, and use new approaches to improve data synthesis.41 However, with our study design presented here is the potential to replicate real-world experiences in application of our findings.41
Fourth, parents of AYAs with cancer are a special population of caregivers, and CSI AYA-Parents is a caregiver-centered special consultation in the setting of standard adult oncology care. On the one hand, we can conclude that AC is an outcome of direct clinical relevance.16–21,28–34 Family caregivers have psychosocial needs that must be addressed so that they can maintain their own health and provide the best care possible to the patient.20 Caregivers are an important part of the cancer care team, and their well-being can be associated with patient-perceived quality of care.67 On the other hand, emotional support coping by the patient can be associated with higher family caregiver depression and anxiety.66 Fifth, a critical point in the terminology of AYA cancer research and an acknowledged limitation of our study is the wide age range represented by a heterogeneous real-life population of patients and caregivers.3–11 On the one hand, significant role changes occur when parents support adult children with cancer.4–8,16–20 However, the impact of cancer on AYA patient functioning, mental health, and psychosocial outcomes should account for the developmental stage or changes at which cancer disrupts these young people’s reality.4–8,16–20,59,60 On the other hand, AYAs diagnosed with cancer often mentally regress and trust parental care again.7,16–20,59,60; they may experience a renewed emotional and practical dependence on their parents.4,5,7 At baseline, 27% of the children with cancer in our study (mean [SD] age, 29.94 [6.3] years) lived with their parents in a household. We assume that the actual age of the adult children plays less of a role than, for example, the parent–child relationship.7,16–20,59,60 We should not equate AYAs without cancer with AYAs with cancer in terms of psychosocial developmental dynamics; it would be fatal to not acknowledge the disruptive psychosocial changes that young adults have undergone after cancer in coping with everyday life.
Conclusions
This investigator-initiated trial broke new ground as the first RCT focusing on supportive care for parents of AYAs with cancer. We implemented strictly research-based methodical criteria with regard to the development and execution of the intervention, recruitment and data strategy, quality management, and primary outcome analysis. However, we were shaken by the reality of AYA families. Nearly 65 months post cancer diagnosis, 65.4% of parents of AYA patients were confronted with a wide heterogeneity of physical, emotional, and household concerns and a need for psycho-oncologic treatment.
In addition to providing research-based methodical criteria, we also applied many features of so-called pragmatic trials.40,41 Thus, patients, clinicians, clinical practices, and clinical settings were recruited as in the real world to maximize the overall transfer of the results of this trial to common practice.36–41
Further studies with a tailored AYA research strategy are clearly warranted. Furthermore, we recommend the evaluation of a psycho-oncologic intervention program for parents of AYAs with nonhematologic malignancies. Further investigations are needed to explore intrafamily health associations and the potential pathways that link these factors. Engaging family caregivers as part of the cancer care team through ongoing psycho-oncologic risk stratification screening and personalized support interventions may improve different patient-reported outcomes in AYA cancer treatment.2–20,29–31,61,62,68 Future research should focus on evaluating the effectiveness of AYA family caregivers’ support and the further development of the best supportive care in AYAs with cancer. In conclusion, the implementation of this novel family-based approach in AYA oncology care may be helpful in reducing the heavy psychological burden of families concerned.
Acknowledgments
Medical writing assistance was provided by John Bean, PhD, Bean Medical Writing, Halle, Belgium, and was funded by Otto-von-Guericke University, Magdeburg, Germany. We thank the parents and their children—our patients—who participated in the study, along with the staff and investigators at the participating study sites.
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