Caring for caregivers in early-phase clinical oncology trials

Early-phase clinical oncology trials (EP-CTs) evaluate the safety of novel treatments for patients with cancer.^1-6 Historically, these trials have presented considerable risks of adverse events while offering limited hope for therapeutic benefit.^1-6 However, recent advances in targeted agents and immunotherapies have led to reduced toxicities and higher response rates.^{1, 2, 7-11} With continued improvements in safety and efficacy, trial enrollment is expected to increase.^{12, 13}

As excitement around EP-CTs grows, renewed attention must be devoted to the challenges they pose.^14-21 To date, concerns around trial enrollment have primarily focused on the patient experience.²² Eligible individuals commonly have advanced disease resistant to standard therapies, limited prognoses, and a substantial symptom burden.^{2, 10, 14, 17, 19, 23-52, 107} Despite progress in outcomes, participants still face inherent therapeutic uncertainty and meaningful risks of adverse events.¹⁴ Furthermore, they must undergo intensive monitoring, frequent health care visits, and numerous examinations and procedures.^{2, 49, 53-55} In these respects, EP-CTs remain a significant commitment, with important emotional, physical, and logistical tolls.

Amid the demanding early-phase setting, informal caregivers face parallel, yet often overlooked, burdens. Alongside their loved ones, caregivers must manage the unpredictability that comes with transitioning to experimental therapies, and balance anticipatory grief with hope for a response.²² To help meet trial requirements, they also assume a wide range of critical and time-intensive roles.^{56, 57} Like other cancer caregivers, those in EP-CTs monitor for treatment effects, assist with medications, provide physical support, and offer emotional care.^58-60 More uniquely, they shoulder complex care coordination, intricate appointment schedules, extensive travel requirements, and considerable financial costs.^{22, 61} Prior work has shown that informal caregiving is associated with an increased risk of mood symptoms, psychosocial distress, and health decline.^{58, 60, 62-74} Thus, in the context of early-phase trials, where trial demands are particularly high, we must ensure that we are caring for caregivers.^{49, 53}

In this article, we examine caregiver experiences during EP-CTs. We begin by describing this population of caregivers and their distinct characteristics. We then discuss their perspectives during trial enrollment and participation, and identify both the responsibilities they assume and the challenges they face. Finally, we provide recommendations to strengthen supports for caregivers and, by extension, those living with cancer.

Understanding the EP-CT caregiving experience begins with a description of those who serve as caregivers. Currently, data characterizing this population are scant, and few studies have included sample sizes large enough to report quantitative metrics.^{29, 59} Despite this, early findings suggest that EP-CT caregivers have distinct features that may predispose to caregiving burden.^{29, 59, 60}

First, EP-CT caregivers diverge from other cancer caregivers in their sociodemographic features. In both groups, individuals tend to be female and middle aged.^{59, 60} However, among the general population, most cancer caregivers provide support for parents (44%) or partners (16%), a minority live with the one they care for (39%), and few work full time (27%).⁶⁰ In contrast, among EP-CT caregivers, three quarters care for spouses or significant others (78%), the majority live with the patient they look after (85%), and a substantial portion are employed full time (42%).⁵⁹ Whether the observed differences relate to EP-CT exclusion of older, frailer patients or other factors will warrant further evaluation. Regardless, EP-CT caregivers appear to face distinct socioeconomic stressors as they live with their loved one, offer support, and manage competing responsibilities.

Second, EP-CT caregivers appear to provide care of greater intensity and duration. Although other cancer caregivers devoted an average of 33 h per week to caregiving tasks, most EP-CT caregivers dedicated at least 50 h per week to performing their duties (72%).^{59, 60} Similarly, whereas the former spent an average of 2 years caregiving, most EP-CT caregivers had already provided oncological care for longer periods of time before enrollment, including nearly one fifth (17%) for over 5 years.^{29, 59, 60} Longitudinally, the provision of prolonged, high-intensity care may affect caregiver strain.

Finally, EP-CT caregivers have unique psychological profiles, even before trial start. In one small cross-sectional study (N = 88), caregivers completing validated questionnaires at phase 1 screenings had higher levels of mood symptoms, stress, and impaired emotional regulation than the general population.⁵⁹ Notably, nearly four in 10 EP-CT caregivers had significant depressive symptoms, as compared to 25% of caregivers supporting patients under palliative care and patients with stem cell transplants.^{59, 75, 76} Mirroring these findings, in a prospective study of 52 dyads enrolling in EP-CTs, spousal caregivers completing a validated inventory exhibited mild trait but moderate state anxiety, which is indicative of a heightened response specific to their situation.²⁹ Delineating relevant underlying concerns, in structured interviews, caregivers reported loneliness, devastation, and fear after learning that standard treatment options had been exhausted.^{22, 29} In sum, by the time caregivers approach EP-CTs, many are already bearing a substantial psychosocial burden.

Given the difficult period surrounding the transition to EP-CTs, supporting caregivers as their loved ones consider trial enrollment is imperative. To date, only a handful of small qualitative studies have described caregiver roles and associated challenges during this time.^{77, 78} However, they highlight three key issues that may impede preparedness for the trial experience: inadequate counseling, limited understanding of trial aims and supportive resources, and varying inclusion in the decision to enroll.^{22, 61}

For the most part, caregiver learning about early-phase trials appears to be largely passive or self directed. Highlighting these themes, in one qualitative study of 19 family caregivers asked to describe their involvement in patients’ decisions to pursue EP-CTs, most caregivers reported gathering information by attending patients’ discussions with their research teams and reviewing consent forms for schedules and side effects.²² Afterward, many turned to additional sources of varying credibility, including lay members of their social networks and the internet, to solidify their understanding.²² Notably, no caregivers reported verbal guidance or receipt of materials outlining their roles and responsibilities.²² Although limited in scope, these data suggest a paucity of material tailored to EP-CT caregivers, which echoes data in general oncology settings, where many caregivers report unmet informational needs.^{60, 79}

Perhaps reflecting these findings, EP-CT caregivers, like patients, often harbor misconceptions regarding trial intent.^{22, 56, 57, 80} In one study of 52 EP-CT dyads, caregivers and patients similarly overestimated the chance for disease stabilization, remission, and cure, with more than half of caregivers perceiving cure as likelier than not.²⁹ Likewise, in a second study of phase 1 caregivers, all respondents endorsed expectations of trial-related medical benefit, and approximately one fifth disclosed hope for cure.²² Concerningly, although all respondents also identified misgivings around potential or unknown side effects, many felt an urgency to act and perceived no alternatives.²² None raised the possibility of concurrent palliative care, although it is unclear whether this alternative was known to them.²² Collectively, these data emphasize substantial knowledge deficits and therapeutic misconceptions, which may influence dyads’ prognostic awareness and predispose caregivers to emotional and practical burdens.

Lastly, caregivers play variable roles in EP-CT enrollment decisions. Generally, both caregivers and patients agree that the final decision should rest with the patient.^{22, 77, 80} Nevertheless, caregivers exert ranging levels of influence. Across trial phases, evidence highlights that familial factors may affect patient conceptions of benefits and burdens, as well as enrollment decisions.^81-83 In phase 1 settings, existing data suggest that nearly all patients discuss their choice with a loved one, and approximately one third identify family as a motivating factor for participation.⁸⁰ However, early qualitative findings also suggest that when EP-CT dyads differ in enrollment preferences, discourse may be variable.^{22, 77} In one study, caregivers who disagreed with EP-CT enrollment unanimously reported keeping their opinions to themselves.²² In another, caregivers articulated their role as supporting the patient and deferring to their preference.⁷⁷ Thus, although caregivers meaningfully participate in conversations around trial involvement, many prioritize the will of their loved one by engaging in protective buffering by withholding concerns, worries, and fears.^{22, 78, 84} Although unexplored in EP-CT settings, investigations in other caregiving populations suggest that such forms of avoidant coping may be associated with anxiety, depression, and quality-of-life changes.^{85, 86}

After trial enrollment, caregivers of patients participating in EP-CTs assume significant and diverse roles.^{56, 57} Similar to cancer caregivers in other settings, they provide emotional reassurance, physical assistance, medication oversight, care coordination, and companionship.^58-60 However, as noted previously, EP-CT caregivers must also manage research-related logistical burdens, heightened therapeutic unpredictability, and variably elucidated toxicities.¹⁴ As existing data underscore, this type of complex caregiving can come with practical, emotional, and physical burdens.^{22, 61, 78}

From a practical perspective, caregivers recognize that EP-CTs require substantial commitment. Quantifying these demands, in one retrospective evaluation of 400 EP-CT participants, patients averaged more than five health care visits per protocol within a 28-day period, had high rates of visits lasting at least 6 h, and commonly traveled over 30 miles to trial sites.⁴⁹ In a different survey of 200 EP-CT participants, nearly half incurred monthly out-of-pocket expenses of at least $1000.⁴³ In both studies, these burdens were unanticipated, which limited dyads’ ability to adequately prepare.^{43, 49} In considering the caregiver experience, in another small cross-sectional study, EP-CT caregivers reported greater financial and schedule-related burdens than other oncology caregivers.^{59, 87} Likewise, in a trial of EP-CT caregivers experiencing mild to severe distress (N = 95), schedule-related burdens were found to be a full standard deviation higher than those reported by general oncology caregivers.^{87, 88} Such time-intensive caregiving can be costly and disruptive. In two qualitative studies of approximately 40 EP-CT caregivers, participants repeatedly identified high transport, lodging, and meal costs as stressors.^{22, 61} Similarly, in structured interviews, caregivers reported less time for household needs and family activities.^{22, 62, 79} In sum, the practical demands of EP-CT engagement often require unexpected and life-altering adjustments.

For caregivers, trial participation also carries unique emotional burdens. As noted, EP-CT caregivers already experience elevated levels of anxiety and depression around the time of enrollment.^{29, 59} Compared to caregivers of patients with cancer in other settings, they also demonstrate moderate impairments in emotional regulation and lower scores on coping scales.⁵⁹ These issues appear to persist longitudinally, with 1-month postenrollment assessments revealing little change in depression, state anxiety, or coping abilities.²⁹ Qualitative studies point to two potential sources of this distress. First, in structured interviews, caregivers commonly referred to concerns for the patient’s well-being by expressing worries over trial effectiveness, possible side effects, and patient decline.^{22, 61, 78} Second, they identified their own responsibility-related pressures by reporting higher levels of stress, family-related burdens, and travel demands in qualitative interviews and quality-of-life assessments.⁶¹

Finally, the question of whether behavioral distress translates into physical symptoms or maladaptive behaviors among caregivers has produced mixed results. Quantitative studies indicate that most EP-CT caregivers view themselves as physically healthy, with self-reported measures of physical functioning, pain, and general health surpassing those of other cancer caregiving groups.⁵⁹ Likewise, caregivers report good global health with little disability both at, and 1 month after, trial enrollment.²⁹ Countering these data, qualitative studies have documented reports of panic attacks, insomnia, and high blood pressure among caregivers.^{22, 61} For example, among 19 EP-CT dyads completing quality-of-life surveys, one third of caregivers endorsed moderate to severe difficulty sleeping.⁶¹ These findings align with broader research on cancer caregivers, where fatigue and sleep-related disruptions are commonly reported, and one in five feels that caregiving has made their health worse.^{60, 89} In future work, the physical dimensions of EP-CT caregiving merit further exploration.

To address the unique challenges faced by EP-CT caregivers, we propose a range of setting-specific research objectives and interventions with the aim of enhancing caregiver support. In acknowledging the high costs and time demands of clinical cancer trials, our recommended approaches are intended to be practical and feasible by leveraging existing infrastructure wherever possible.

Leah L. Thompson: Conceptualization; investigation; writing–original draft; writing–review and editing; supervision. Caterina S. Florissi: Conceptualization; investigation; writing–original draft; writing–review and editing. Debra Lundquist: Supervision; writing–review and editing. Rachel B. Jimenez: Supervision; writing–review and editing.

The authors declare no conflicts of interest.