PEDIATRICS Vol. 114 No. 3 September 2004, pp. 852-855 (doi:10.1542/peds.2003-0913-L)
COMMENTARY |
Palliative Care: A Supportive Adjunct to Pediatric Phase I Clinical Trials for Anticancer Agents?
Department of Clinical Bioethics,
Warren G. Magnuson Clinical Center
National Institutes of Health
Bethesda, MD 20892
Hampering enrollment of children to phase I oncology research would dramatically impair the ability of investigators to develop new treatments to improve medical care for the pediatric cancer population. The variability in pediatric tumor response indicates a need for the development of new anticancer agents that specifically target varying histologies of malignancies.1 Aleska and Koren argue that "clinical trials may be the only way to determine the appropriate types of treatments for pediatric cancer."2 The primary scientific objectives of a phase I trial are to assess the safety and tolerability of tested agents, to identify the maximum-tolerated dose of the drug, and characterize the drug's pharmacokinetics.1,3–8 Secondarily, preliminary antitumor efficacy data are sought.1,3–8
However, enrolling children with cancer in phase I trials raises important ethical concerns. Although pediatric clinical investigators hope that participation in the phase I trials will help subjects, they are not meant to cure or even improve the condition of the child. Usually, however, they offer the only remaining treatment option for children with advanced cancer and thereby provide an important source of hope at a difficult time.
Similar to adult phase I trials, pediatric phase I trials generally have a 5% to 8% response rate.1,3–8 Thus, it may be questionably unreasonable to offer enrollment in pediatric phase I trials because the likelihood of risk and discomfort are disproportionate to the marginal benefit. These trials may raise unrealistic hopes of a cure, burden already sick children with potentially invasive procedures, compound suffering through chemotherapeutic and other associated drug side effects, and limit the opportunity for palliation. On the other hand, families may perceive even a low likelihood of benefit favorably, and ethically we ought to respect the family's prima facie right to make this determination. As Ackerman notes "adequately informed families may choose to participate in a phase I trial and this decision may genuinely reflect their values and goals."8
It is equally important that we should avoid an environment in which research investigators and parents believe they must choose between enrollment in the research trial and palliative or end-of-life care for their child. Does a false dichotomy exist whereby palliative or end-of-life care is not perceived as compatible with phase I trial participation?9 Is this an artificial problem? Agrawal and Danis contend that "research subjects with terminal illness should not have to forgo the standard of care in palliative medicine in the course of enrolling in research."9
Is there some way to combine enrollment in pediatric phase I trials with palliative care services? Families who choose research for their child will still be in need of the components of comprehensive palliative care including psychosocial support, symptom and pain management, spiritual comfort, and counseling.10 Palliative care addresses quality of life at the end of life and represents a holistic approach to caring for patients whose disease is refractory to curative measures. Palliative care is not, however, inimical to research participation.10 Combining phase I trials with palliative services would not only offer pediatric patients and their families who choose this option some chance of hope along with the best end-of-life care but also afford investigators the opportunity to test potential new therapies that may benefit the enrolled child or future children.11,12
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It is arguable that the combination of pediatric phase I trials with palliative care services seems virtuous; it is the right and good thing to do. Certainly the illness of a child thrusts the parent(s) and the child into a situation that is fraught with uncertainty, emotional unrest, and confusion. Parents must absorb difficult and often devastating information and at the same time determine the best course of action for their child. Children become eligible for phase I trials when their disease is refractory to standard therapy or when no curative therapy exists.1,3–8 Given this stage of the child's illness, parents should not have to choose between phase I trial enrollment and palliative support. However, parents may not perceive palliative care as a direct interventional measure or a means to provide benefit but instead as inferior or an alternative that suggests "giving up" or "giving in" to the imminent death of the child. Additionally, the psychological burden of "giving up" may be too great for some parents to consider. Because the outcome for children enrolled in phase I trials is uncertain, pediatric oncology investigators skilled in palliative care and pain management may help to address potential risks of phase I trials, symptoms associated with the child's progressive disease process, and psychosocial concerns that may arise during research enrollment.
In a recent study of parental perceptions of their children's participation in phase I oncology trials, 62% of parents indicated that they did not define participating in the clinical trial as a decision, because the alternative of no treatment was not acceptable to them. Their expectations included providing treatment to prolong the child's life or "buying time" for a potentially new therapy, prolonging the time with their child, hoping for a cure and/or miracle, and helping other children.13
Parents may perceive the slightest benefits of the research to include those effects that may be immediately tangible such as the possibility for tumor regression in a solid tumor that has been refractory to previous treatment. Benefit may be more elusive, such as the value of added time, allowing the child the opportunity to spend time with his/her family and friends outside of the clinical environment and the daily regimen of the research protocol. Although survival time may only be minimally prolonged, if at all, to a parent, this is still cherished time. Tumor regression and a stable disease are beneficial goals, therapeutic, and in the child's immediate best interest. For terminally ill children who have experienced multiple relapses, the benefit may simply be improved quality of life. However, as families consider phase I trials as the last available treatment option for their child, they may be unable to acknowledge their child's suffering as they pursue cure to the end.14
In 2000, the American Academy of Pediatrics called for integrated models of care so that children can receive palliative services early in the process of their illness.15 However, pediatric palliative care remains fragmented because of the lack of empirical data surrounding the effectiveness of these services, the unpredictability of survival estimates, reimbursement issues, and a lack of pediatric palliative care expertise within clinical and research facilities.15 Unfortunately, the majority of health care professionals have not been formally trained in end-of-life care.16 Hilden et al16 reported that only 10% of pediatric oncologists in their study had a formal course in pediatric terminal care, with nearly half (48.3%) of oncologists reporting a lack of access to an available palliative care team. Moreover, only 53% of respondents initiated a discussion of advance care preferences with their patients and families, with the family's unrealistic expectations "always or often" cited as a factor affecting the end of life. Without palliative support and a lack of training to discuss palliative and/or end-of-life care with pediatric phase I participants and their families, a "window of opportunity" may be lost to ensure a transition from the potential benefit that the research trial represents to symptom management and palliative care. As such, parents may continue to embrace a goal of cure for their child that is not likely obtainable through phase I research.
Investigator competency and skills in palliative care may impact the patient and parents' expectations of the trial, provide for some sense of control in end-of-life decision-making, and may provide a nonjudgmental, supportive climate to discuss advance directives and quality care for these children. Affording parents and the child the opportunity to share their experiences, fears, and concerns about the clinical diagnosis, prognosis, and research course may set the stage for a trusting relationship between the child, family members, and health care providers. von Gunten et al17 suggest setting goals of care with patients and their families by asking open-ended questions to elicit perceptions of aggressive care, life-sustaining measures, research termination, hospice options, and bereavement care. Consistent, frequent, and honest communication is a key component to allaying emotional and/or physical distress as well as unrealistic expectations.
Although the immediate goals of the research and palliative care teams may conflict, both seek to achieve the best possible outcomes for children: the generation of knowledge to advance medical therapies for pediatric cancer patients as well as interventions to lessen concomitant suffering through the provision of quality compassionate care. Why, then, should they not be combined? Designing phase I trials with the concurrent use of pediatric palliative care support should be considered. At the very least, every researcher should encourage families to access this type of support during the research trial if a palliative service exists.
Nonetheless, some may challenge that combining phase I trials with palliative support may be the only avenue for parents to receive palliative support for their child. Would the availability of palliative supportive care in combination with the research trial create an undue influence into research participation? Would the additional support of palliative care provide a superior standard of care for research participants than what is currently provided off protocol?18 We present this possible objection but believe it is not well founded. It is well documented that symptoms associated with a child's advanced cancer may include pain, fatigue, nausea and vomiting, and other associated maladies; similarly, drug-related nonhematological toxicities may also include some of these symptoms.19,20 On the other hand, the current paucity of palliative support for children with cancer may influence families to choose research as the only "active" option.
Although the management of toxicities associated with phase I trials are dictated by research protocol, palliative services that augment the clinical trial may address pain management and other types of supportive measures imperative for the child's comfort and quality of life. Second, individuals participate in research for a myriad of reasons and are subject to many influences.21,22 We believe that the combination of palliative support with pediatric phase I trial participation does not exceed the threshold of what may be considered undue influence: it is not excessive or inappropriate. Working together, researchers and palliative care specialists can improve the child's research course by identifying divergent views associated with the research aims, continuously examining the risk/benefit ratio, and evaluating the feasibility of research continuation.
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CONCLUSIONS AND FUTURE RECOMMENDATIONS |
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TOPLINKING PEDIATRIC PHASE I...CONCLUSIONS AND FUTURE...REFERENCES |
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The ethical complexities associated with phase I clinical trials will remain as we carefully establish safe and tolerable doses of investigational agents to improve cancer treatment for the pediatric population. Influencing the direction of children's health through scientific research will benefit children in the future; honest and direct communication regarding the likelihood of benefit in phase I trials, ethical reflection and sensitivity, creativity in scientific design, and multidisciplinary approaches are needed to address the importance and inclusion of palliative measures for children with advanced cancer who are enrolled in these research trials. It is undeniable that for all parties who are intimately involved in the care of these children, end-of-life issues remain difficult. However, by explicitly incorporating palliative care support throughout the child's research course, we assist parents and their children to determine their best course of action at each stage.
Ongoing research should strive to enhance understanding of the perceptions of parents and their children who are enrolled in phase I oncology trials, including their benefit expectations and reasons for enrollment; psychosocial issues associated with complex decision-making and the care of an incurably ill child; and their understanding of risk and available supportive options such as palliative care. Research should also focus on researchers' and pediatric oncologists' perceptions of the role of palliative care services in pediatric research trials as well as their comfort level in discussing and accessing these services for children. This would provide a better understanding of the benefit, use, and outcomes associated with palliative services in combination with clinical trials. To this end, we open a dialogue for the betterment of terminally ill children and their families enrolled in cancer clinical trials, as well as for the scientific community.
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ACKNOWLEDGMENTS |
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We acknowledge Manish Agrawal, Gwenyth Wallen, and Janet Deatrick for thoughtful comments on earlier versions of this manuscript.
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FOOTNOTES |
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Accepted Mar 8, 2004.
Reprint requests to (C.M.U.) School of Nursing and Center for Bioethics, Room 357 NEB, 420 Guardian Dr, Philadelphia, PA 19104-6096. E-mail: culrich{at}nursing.upenn.edu
The opinions expressed in this article are the personal views of the authors and do not reflect the official policies or positions of the Department of Health and Human Services, National Institutes of Health, or Public Health Service.
Dr Ulrich's present address: School of Nursing and Center for Bioethics, Department of Medical Ethics, University of Pennsylvania, Philadelphia, PA 19104-6096.
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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