End-of-Life Childhood Cancer Research: A Systematic Review

A protocol was developed a priori, following the Enhancing Transparency in Reporting the Synthesis of Qualitative Research and Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements.^24,25  A literature search was designed and conducted with the aid of a health librarian by using Ovid Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Web of Science, and ProQuest (inception to August 19, 2020). The search strategy (Supplemental Tables 5 and 6) included subject headings and keywords for the following concepts: (1) children and adolescents, (2) cancer, (3) clinical trials, and (4) terms relating to perceptions, understanding, and decision-making.

Included studies were focused on perceptions or experiences of research participation for children and adolescents with cancer at the EOL from the perspectives of pediatric patients with cancer (<21 years), their parents or guardians, or HPs involved in caring for this population. EOL research participation was defined as the enrollment in research studies by children whose cancer was no longer thought to be curable by standard treatments within what was thought to be the last few months of life. This encompassed any type of research, including palliative care and symptom management studies as well as studies of anticancer treatments. For studies to be included, there needed to be a discussion explicitly about research enrollment and not just the broader topic of EOL decision-making. Exclusion criteria were as follows: (1) studies that were not fully published peer-reviewed studies (conference proceeding or gray literature), (2) review articles or editorials, (3) studies that were not published in the English language, (4) duplicate publications, (5) studies that included adult patients in which results relating to patients <21 years of age could not be extracted separately, (6) studies that included non-EOL research in which results related to EOL research could not be extracted separately, and (7) studies that were focused on EOL decision-making in general without an explicit discussion on decision-making about EOL research. The search was supplemented by examining the bibliographies of included studies. Two authors (F.H. and L.W.) independently screened titles and abstracts to identify potentially eligible studies. The full text was retrieved for these studies and evaluated for eligibility by the same 2 reviewers who applied the eligibility criteria.

Two investigators (F.H. and L.W.) independently extracted data and appraised studies using piloted forms. Studies were classified as qualitative or quantitative (survey-based or retrospective case series). Relevant criteria from 3 tools were used for study appraisal: the Consolidated Criteria for the Reporting of Qualitative Evidence checklist for qualitative studies,²⁶  the British Medical Journal Critical Appraisal Checklist for a Questionnaire Study²⁷  for survey-based studies, and the Joanna Briggs Institute Critical Appraisal Checklist for Case Series.²⁸  No study was excluded because of quality.

Two investigators (F.H. and L.W.) inductively coded the text included in the results section of each (qualitative or quantitative) article line by line. Thematic synthesis was performed by first grouping codes into descriptive and then analytic themes, with translation of themes across studies.²⁹  The authors independently performed initial analyses, then developed the synthesis together through iterative discussion.

Any disagreements in study selection, data extraction, quality assessment, and synthesis were resolved by discussion. Conflicts in study selection and other review procedures were resolved through discussion with a third reviewer (K.W.).

A total of 15 203 articles were identified, of which 24 were included for analysis (Fig 1). One of the 24 included articles was categorized as a palliative care research study, whereas the remaining 23 studies were categorized as phase I anticancer treatment studies. Qualitative methods were used in 11 articles, whereas quantitative methods were used in 13 articles, 11 of which were surveys and 2 of which were retrospective case series (Tables 1–3). These 24 studies included 1787 participants (162 patients aged 6–21 years old, 904 parents, and 721 HPs). One study included 2 surveys, but the number and type of individuals participating in the second survey were not reported.¹⁴  Similarly, the authors of a retrospective case series reported the perspectives of HPs without stating how many HPs’ views were described.³⁰ 

The 11 included qualitative studies met between 10 and 22 of the 32 items on the Consolidated Criteria for the Reporting of Qualitative Evidence checklist (Supplemental Table 7).²⁶  Four of the survey-based studies included some qualitative findings; thus, 26 quality criteria in the British Medical Journal checklist were relevant, and 11 to 14 were met (Supplemental Table 8).²⁷  The remaining 7 survey-based studies were purely quantitative and met 7 to 21 of 24 relevant criteria. Survey instruments were only available for review from 4 studies.^31–34  In all the studies, a new survey or a preexisting, unvalidated survey was used or a previously validated survey was adapted without revalidation. The 2 case series met 2 to 7 of 7 quality criteria in the Joanna Briggs Institute checklist (Supplemental Table 9).²⁸ 

Eight themes were identified (Fig 2, Table 4).

Many parents and patients considering phase I studies actively searched for cancer treatment options but believed that these options were increasingly limited (or nonexistent).^7,35–40  They had exhausted any curative treatments and now perceived the decision to be “phase I or nothing.”^7,36,39,40  In contrast, HPs did not espouse the idea that families participated because of a lack of choice and talked of presenting families with options, including palliative care.^{7,33,34,38,41,42}  Despite this, many families did not feel that palliative care alone was a viable alternative.^39,40 

Parents and patients participated in phase I trials to access treatment with even a remote chance of keeping the child alive.^7,36,42,43  Regardless of the final outcome, they needed to know that they had not given up.^7,36,37,43  HPs were conscious of families’ desires to try anything,^{7,32–34,40,41,43,44}  perceiving it to be a significant barrier to informed consent.³⁴ 

Many parents and patients alluded to expected poor outcomes.^{7,36–38,40,42}  Some talked of miracles while recognizing that the chances of a cure were low.³⁶  Other parents only questioned their research participation after they saw their child decline or fail to improve on study.³⁶ 

For many patients and parents, the desire to try anything was motivated by optimism; predominantly hope for a cure.^{7,35–37,40,42,43,45,46}  Others knew that currently available trials were unlikely to offer a cure but participated in the hope that their child might survive until a cure became available.^35,36,47  For a smaller number of parents and children across multiple studies, participation was motivated by other desires, such as hopes for prolonging life^{7,35–37,40,43,48}  or improving symptoms.^7,36 

HPs commonly described symptom improvement as a reason to enroll children in trials^31,41,42,44  but did not discuss longer life or a cure as a potential benefit.³⁴  However, HPs were aware of families’ desires to maintain hope for a cure through research participation.^{7,31–34,41,42,44}  A minor theme expressed by HPs across several studies was the ethical concern that offering families phase I trials may encourage false or unrealistic hope.^{31,32,41,44,49}  These HPs identified difficulties in ensuring realistic expectations, particularly when obtaining consent for research participation.^33,34  Some HPs talked of encouraging families to focus on more achievable goals than a cure, for example, symptom relief or a peaceful death.⁴² 

Despite hoping to benefit from trial participation, many parents and children expressed concern about whether participation was ultimately the right decision for them and about the possible outcomes.^35,36,40,47 

A small number of parents and children, but not HPs, discussed the role of religion and spirituality in guiding decisions and sustaining hope.^{7,35,36,40,45,46} 

This theme was discussed only by parents. According to some participants, a “good parent” was an expert on their child: extensively researching potential treatments and protecting and advocating for their child while considering the opinions of others, including their child, family, and HPs.^{7,36,37,40,42}  Many parents perceived the ongoing quest for a cure to be a fundamental aspect of this role, only considering noncurative options once a cure seemed impossible.^36,38 

Again, this concept was only described by parents. Parents talked of “doing right” by their child: considering the facts and making decisions that put the child first.^7,37,40,43  In particular, although many parents had altruistic goals for research participation, they prioritized their child’s well-being.^7,37,43 

Many children and parents hoped to help others through research participation.^* Some families stated expressly that it was acceptable for HPs to mention possible benefits for other families and participated with this intention.⁴⁸  Some wished to prevent others from experiencing the suffering they had lived through.⁴³  They valued research and sometimes hoped to help HPs out of gratitude.^14,45,46,50  In contrast, HPs believed that families made decisions in their own child’s interest, with benevolence playing a minor role.^32,41  Many HPs avoided discussing this topic with families altogether.^33,34 

A minority of parents talked about helping others through research participation as a way of finding meaning in their experience, particularly after their child’s death.^7,36,37,40  In contrast, HPs rarely discussed meaning or considered it to be a benefit of participation.⁴¹ 

Parents discussed time pressures inherent in phase I enrollment: limited spaces in trials necessitated quick decisions, constraining their ability to consider the options.^36,42  Other fears included their child’s possible deterioration before receiving trial medications or failure to meet study requirements, losing their place.^36,40,42  Some parents coped by making one or more contingency plans.³⁶  HPs were aware of this parental urgency.⁴² 

All 3 types of participants considered the possible effects of studies on quality of life (QoL).^† Some chose research participation hoping to improve QoL,^7,35,36,38  whereas others tolerated possible temporarily decreased QoL to allow study involvement.^7,35  Still others chose not to participate, fearing reduced QoL due to side effects, invasive procedures, or psychological suffering.^{7,30,37,45–48,50}  Families considered their children’s current state of health and ability to tolerate further treatment, sometimes deciding against study enrollment for children who were unwell or symptomatic.^7,14,36,51  HPs perceived that potential toxicity was a common reason for families not wanting to participate.^6,31 

Parents, and to a lesser extent, children and HPs, referred to practical facilitators of enrollment.^36,37,44,52  Parents felt comfortable with their children receiving treatments they had previously been given in hospitals known to them.^36,37  Transferring care to another medical team to facilitate research participation meant having to retell their story, establish new relationships, and deal with possible miscommunication between teams.¹⁴  Time spent in the hospital^7,14,48,50  (particularly at short notice), traveling to receive treatment,^36,50,52  and interruptions to family life⁵⁰  were other barriers to enrollment.

Parents and children appreciated receiving study information before discussions with HPs.⁵²  They valued the opportunity for multiple meetings^33,34,42,52  in comfortable locations⁵²  and having time for decision-making.^7,42,52  Families welcomed having easy access to HPs when questions arose.⁵² 

Parents and children described consent as involving large amounts of complex oral and written information.^42,52  They preferred succinct, forthright language that was tailored to their needs in quantity and complexity.^42,52  Families appreciated receiving multiple forms of information (eg, verbal, pictorial, and written) to suit different learning styles.⁵²  HPs agreed that consent processes, specifically paperwork, were lengthy and complex, in part because of regulatory requirements.^31,32,34,44 

Families appreciated that HPs discussed certain issues during the consent process: summarizing the child’s previous treatment and current status,^38,52  clarifying the options,^36,52  and providing details about individual trials,^35,38,52  particularly about how other participants had fared.^7,35,36,52  After consenting to participate, families desired regular, timely trial updates.⁵² 

HPs believed that parents grasped basic aspects of phase I studies, such as confidentiality, the right to withdraw, potential toxicity, and alternative options.³⁴  However, they perceived that parents misunderstood complex concepts, such as dose escalation.^33,34  Many HPs believed that families overestimated the likelihood of their children benefiting from participation^31,44  and failed to comprehend the goals of phase I studies.^32,34,44  Consistent with this belief, in one study, adolescents participating in phase I research claimed to understand study information but overestimated their chances of benefiting from participation.³⁵  In another study, parents showed poor understanding of risks, benefits, and alternative options.³⁹ 

In general, HPs were aware of the goals of studies,^31,32,41,44  but HPs working in different settings held different perspectives about phase I trials. Nurses were less likely than physicians to accurately perceive study goals and the probability of benefit or toxicity.^32,44  HPs working in phase I consortium centers were more confident than those working outside these centers that trials benefited participants without causing false hope.³¹  British oncologists expressed greater ethical concerns regarding phase I trials than US oncologists.⁴¹ 

Many families looked to HPs^7,38  for advice that was consistent with their values.^36,42,52  Often parents sought validation of their choices for fear of making wrong decisions.^7,36  Many parents who chose experimental therapy, hoping for a cure, expected the backing of their HPs.^7,36,37  Regardless of their choice, parents sought assurances that their child would receive the same standard of ongoing care.^7,37,38  Some parents stated that HPs had previously provided treatment recommendations, and so they wanted advice, but these HPs felt parents should make the choice in this situation.^36,42,52  HPs referred to families’ needs for general multidisciplinary care but, despite parents’ desires for direction, preferred to avoid making specific recommendations.^31,34,41  Some parents and HPs described physicians as holding simultaneous roles as clinicians and researchers.^40,49  Both groups were aware of a potential role conflict, but parents hoped that HPs would prioritize their child despite their own research interests.⁴⁰ 

Most HPs had only received informal instruction on taking informed consent for research participation, generally by observing senior colleagues.^33,34  Many HPs believed that formal education would be beneficial.^33,34 

HPs generally had positive perceptions of phase I research, believing that it was appropriate to respect family preferences to participate.^31,41,44  A minority described ethical concerns, including the lack of benefit for participants, families’ unrealistic expectations, and misunderstanding of the purpose of studies.^41,44  Few HPs described experiencing moral distress secondary to patients’ involvement in phase I studies.⁴⁴  Any impact of the tension HPs felt between clinical and research roles was rarely discussed.⁴⁰ 

The child’s role in the research consent process was a common theme. Parents and HPs talked of graded participation,^34,39,40,46  with parents making choices on behalf of the youngest children,^{34,39,40,46,48}  considering older children’s preferences,^{7,14,31,37–40,43}  and allowing the oldest children to choose for themselves.^{32,35,39,44,48}  Many HPs suggested that although children could decide, often it was parents who did decide^33,34  or the children deferred to parental preferences.⁴⁴  Decision-making conflict was infrequently discussed,^45,48  although parents in one study were more willing to accept their child’s request to participate in research against parental wishes than their refusal.⁴⁸ 

This review brings together patient, parent, and HP perspectives on the topic of EOL research in pediatric oncology, with the intention of providing clinically relevant guidance to these groups.

Parents of children with incurable cancer and the HPs who treat them may find it helpful to discuss how other families make decisions about EOL research. We found that many parents sought a sense of control at the EOL by making choices but experienced a somewhat contradictory position as the choices available to them increasingly diminished. Despite sometimes being presented with several choices, many parents only considered options that were associated with a chance of a cure, however small. The implication is that for many parents, palliative care without anticancer treatment was not a worthwhile choice.

Families making decisions about EOL research may also benefit from hearing of other families in our review who considered the practical inconveniences of research and potential interference in QoL and chose not to participate.

At times, differences of opinion arise in clinical practice as to whether research participation is in the interest of a particular child. We sought to identify differences in views of EOL research between children, parents, and HPs because understanding divergent perspectives may help HPs to manage conflict. One area of difference was perceptions of hope. Hope for a cure was commonly cited by families searching for any available treatment option. However, other hopes were also described and valued, such as hope for symptom relief. These findings echoed the results of other studies revealing the importance of hope in promoting resilience for families of children with cancer.^53–56  In contrast, a small proportion of HPs in our review were concerned about familial hope. These HPs feared that consent could never be truly informed when participants were so determined to access treatment. Fewer HPs worried that hope could be false and that families may be acting under therapeutic misconception.^19,57 

These differences in families’ and HPs’ conceptions of hope are reflected in the broader literature.^58–60  Whereas families may experience different types of hope, HPs typically focus on a limited vision of hope, such as hope for a cure.^58,59  When a cure is unlikely, HPs may worry that hopeful families are unrealistic and will pursue aggressive treatments at the EOL, leading to children suffering.^53,58–61  It may help HPs to understand that for many parents, hope and the ongoing trial of new treatments was a key aspect of being a “good parent.” This is consistent with related studies, notably the ethnographic study by Bluebond-Langer et al⁶²  in which parents felt driven to pursue further treatment up until days before their child’s death.^53,54  Similarly, in the study by Tomlinson et al,^53,54  parents of children with incurable cancer were more willing than HPs to accept chemotherapy for children at the EOL, even if treatment compromised QoL. Although there is some literature that demonstrates an association between hope, delayed prognostic understanding, and aggressive EOL care, the findings of our and other studies suggest that parents can simultaneously be hopeful but also understand the prognosis.^59,60 

We also identified differences in the ways that families and HPs approached altruism and legacy. While prioritizing their child’s interests, families found meaning and legacy in altruism. This is consistent with previous studies in adult and pediatric oncology.⁶³  In contrast, we found that HPs were reluctant to discuss altruistic motivations for research participation, despite the primary intent of research studies to benefit future patients.⁶⁴  Similarly, HPs avoided guiding parental decision-making, although many parents desired guidance and support. It may be that HPs hesitate to influence parents or to discuss altruism for fear of coercion.^65,66  However, the nature of phase I research means that discussions about altruism could be considered to be a critical aspect of informed consent and may help to avoid therapeutic misconception.^66,67 

Lastly, we explored the perceptions of families and HPs regarding EOL research so that researchers may use this information to guide study processes and design. Children, parents, and HPs all found informed consent processes for phase I trials to be challenging because of the requirement to transmit large amounts of complex information, often in short periods of time. Unsurprisingly, this was associated with a perceived lack of research participant understanding. These findings are supported by the broader literature on understanding in participants across adult and pediatric research.^68–71  We identified several possible improvements to the informed consent process, including the need for formal training of HPs in taking research consent.⁷⁰  More research is needed on the child’s role in the consent process.

Although we hoped to provide guidance that was grounded in child and adolescent perspectives of EOL research, it is important to note that a majority of participants in the included studies were parents and HPs. Therefore, the perspectives of patients were under-represented. It may be that researchers hesitated to approach young people about a potentially sensitive topic. However, our findings indicate that children and adolescents played an increasing role in decision-making with age and that many were willing to discuss their perspectives in studies included in this review. We would suggest that future researchers should investigate these perspectives further.

A particular strength of this review is the inclusion of data from a broad range of perspectives, permitting comparison of the views of a range of stakeholders and identifying areas for practice improvement.

Despite conduct of a broad and systematic search, we only identified 1 study in which palliative care research was evaluated. This may be due to a lack of both palliative care research and studies in which stakeholder perceptions of it are examined. Our findings therefore relate primarily to phase I studies. Although many HPs were included, this was usually in survey-based studies, limiting the depth to which their opinions were explored. Although qualitative methods were used in several included studies, they usually provided only thin descriptions and limited data.^72,73  The inclusion of heterogeneous data presented a challenge for synthesis.

Children with cancer, their parents, and the HPs who treat them hold a broad range of perspectives regarding EOL research participation. Considering these perspectives and how they differ can help guide clinical and research practice. More research is needed to understand how these stakeholders, particularly the children themselves, view palliative care and other EOL research studies.

We thank Tamsin Adams-Webber and Quenby Mahood for designing and performing the literature search. We also thank Dr Angela Punnett for advice on the conduct of the study and for reviewing the manuscript.

EOL

end of life

HP

health professional

QoL

quality of life