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Phase I pediatric oncology trials
Ethical Issues Phase I Pediatric Oncology Trials Terrence F. Ackerman, PhD
D
ESPITE TREMENDOUS STRIDES in the development of chemotherapy for childhood cancer, current failure rates continue to spur the search for drugs with greater efficacy and safety. A drug showing promise in laboratory and animal studies is first administered to humans in a phase 1 clinical trial. The primary objectives of the trial are to determine the maximum tolerable dose of the drug and to develop a preliminary profile of its toxicities. The search for the maximum tolerated dose reflects the assumption that cancer chemotherapy is most likely to be effective at a toxic but tolerable dose. The design of a phase 1trial involves an escalating dose scheme in which each successive group of subjects is treated at a higher dose. The first group receives a dose unlikely to be either toxic or beneficial, and the dose level for each subsequent group is increased until a maximum tolerated dose is identified. Subjects are incurable patients whose cancer has proven refractory to more established forms of treatment, but whose performance status is still sufficiently strong to undergo additional chemotherapy. lnformation regarding the maximum tolerated dose and prominent toxicities is used to define the appropriate dosing for subsequent trials of the drug’s efficacy. Phase 1 trials of a new drug are usually initiated in adult cancer patients. They must be repeated separately for children because drug pharmacokinetics may differ in pediatric subjects. For example, the maximum tolerated dose is usually higher in children than adults. In ad-
From the Department of Human Values and Ethics, College of Medicine, University of Tennessee, Memphis, TN. Address reprint requests to Terrence F. Ackerman, PhD, Department of Human Values and Ethics, 956 Court Ave, 8324 Coleman Bldg, College of Medicine, University of Tennessee, Memphis, TN 38163. 0 1995 by Association of Pediatric Oncology Nurses. 1043-4542/95/l 203-0010$03.00/0
Journal
of Pediatric
Oncology
Nursing,
dition, severe and dose-limiting toxicities are sometimes different for adult and pediatric patients. These disparities prevent formulation of an appropriate dose for child cancer patients based on adult phase 1 studies. Despite the necessity of phase 1 trials in children, ethical issues have persisted regarding their conduct. A basic question is whether the administration of chemotherapy in a phase 1trial can be undertaken with “therapeutic intent.” Because the toxicities of the drug may expose children to serious risk of harm, its use cannot be morally justified if considered a nontherapeutic procedure. Moreover, even if administration of chemotherapy in a phase 1 trial is properly regarded as therapeutic, its moral acceptability depends on whether it promotes the best interests of subjects. In addition, involvement of children in a phase I study requires that investigators be able to secure the understanding and free agreement of the parents and of the children who are capable of assent. Some critics have doubted that any of these conditions can be satisfied, and their concerns require serious examination. The first issue is whether administration of phase 1 chemotherapy to pediatric subjects should be considered a therapeutic research intervention. Commentators who reject this position point out that the purpose of a phase 1 trial is to explore the tolerable limit of the drug’s toxicities and is not to evaluate its efficacy in achieving remission. They claim that the escalating dose scheme, starting with a conservative dose unlikely to cause serious toxicity, virtually assures that early subjects will not achieve remission. Moreover, they assert that there is no reasonable expectation of therapeutic success, given that retrospective analysis of pediatric phase I trials reveals a response rate (complete and partial) under 6%. However, there are good reasons for viewing Vol 12, No 3 (July),
1995: pp 143-145
143
144
Terrence
administration of chemotherapy in a phase I trial as a therapeutic intervention. Although the objective of the study is to establish a maximum tolerable dose, this does not preclude the additional goal of providing therapeutic benefit to subjects. Moreover, when subjects suffer from progressive disease refractory to more established forms of treatment, any chance for further remission might be viewed as offering reasonable expectation of success. Finally, there are potential therapeutic benefits other than disease remission, including stabilization of disease progression, reduction in pain symptomatology and maintenance of hope. If administration of phase I chemotherapy is properly considered a therapeutic intervention, two important criteria (encoded in the federal regulations on pediatric research) must be satisfied to establish that it promotes the best interests of subjects. One is that the risks to subjects are justified by the intended benefits. The other is that the risk/benefit ratio of chemotherapy is as favorable as that of any alternative strategy for managing the disease. In weighing the risks and benefits, several considerations are pertinent. The potential benefits include the slight chance of disease remission or stabilization, maintenance of hope, reduction of pain or discomfort and, for some older children, altruistic satisfaction of contributing to the development of new treatments. The risks of harm include lethal complications of the chemotherapy, which occur in somewhat less than 3% of subjects in pediatric phase I trials. More common, nonlethal complications include infection, bleeding, impaired renal and hepatic function, and nausea and vomiting. There is also the added pain and discomfort from diagnostic procedures used to monitor drug toxicities. Finally, additional time in the hospital may be necessary due to side-effects of the drug. The risk/benefit ratio of participating in the phase I trial must also be compared with the advantages and disadvantages of managing the child’s illness through the provision of palliative care only. Although the latter alternative precludes the opportunity for any further remission, it might possess several advantages. The child would be spared any suffering associated with the provision of additional chemotherapy. The
E Ackerman
child would avoid the pain and discomfort involved in the diagnostic procedures used to monitor drug toxicities. In addition, suspension of further chemotherapy might allow more time at home before the child’s death. These advantages would be conjoined with care focusing on relief of the symptoms and complications resulting from disease progression. Determination of whether the risks of participating in a phase I trial are justified by the anticipated benefits, and whether the risk/benefit profile compares favorably with palliative care, cannot be settled merely by enumerating the factors cited above. These judgments require assignment of a relative weight or importance to these considerations. For example, the risk/ benefit assessment of receiving phase I therapy depends on whether the slight chance of further remission is assigned greater weight than the possible discomforts and dangers associated with treatment toxicities. Similarly, the comparative advantages of chemotherapy or palliative care depend partly on the relative importance assigned to brief remission of disease versus the opportunity to spend more time at home. These judgments can only be made relative to certain values and goals. Because the consequences of the decision must be borne by the child and parents, it is their values and goals that should determine the relative weight of these factors. The judgment of what serves the child’s interests will depend on drawing out a clear understanding of the values and goals important to the family at this point in the child’s illness. This conclusion suggests that the appropriateness of the decision to enter a child in a phase I trial will depend on the adequacy of the informed consent process. Assurance that the decision reflects the values and goals of the family requires that it be both fully informed and free from serious affective constraints. An adequately informed decision involves the provision of key items of information. The family must understand the purpose of the phase I trial and the very low probability of further remission of the child’s disease. The number and types of monitoring procedures required must be clearly delineated. Uncertainties about the toxicity of the dose level used must be explained. Perhaps most importantly, there must be a candid and complete discussion of the merits and disadvan-
Phase
tages of participating in the trial compared with managing the child’s disease with palliative care measures. These considerations must be discussed within the framework of the basic understanding that the child’s cancer cannot be cured and that even an extended remission is no longer a realistic prospect. Adequately informed families may choose to participate in a phase 1 trial and this decision may genuinely reflect their values and goals. They may feel that it is not yet time to give up hope of further remission. The child may feel reasonably well and be willing to accept the rigors of additional chemotherapy. Both parents and child may find satisfaction in contributing to the development of new treatment. For many families, participation will be the most suitable way to act on the considerations most significant to them. Nevertheless, there are troubling affective constraints that can impair the decision making of child and family. By affective constraints, I mean psychosocial factors that skew the ability to make a decision that genuinely reflects their values and goals. In the case of preadolescent children, the affective constraints involve their limited capacity for independent decision making. Studies in developmental psychology clearly show that preadolescent children have a weak sense of control over interventions in their lives and a strong need to conform to adult expectations. Different affective constraints are encountered with adolescents. They may feel guilty about “failing” their parents by having an incurable disease, and are often highly concerned to do what will please their parents or ease their burden of suffering. They may believe that their parents’ ability to deal with their illness will be enhanced if another therapeutic intervention is attempted. An important implication of these affective factors is that children who are weary of treatment may be inclined to not articulate their reservations if parents and caregivers are strongly in favor of their participation in the phase I trial. Thus, their participation may not reflect their own values and goals. A different set of affective constraints may im-
I Trials
145
pinge on the decision making of parents. As their child’s disease proves refractory to more established forms of treatment, parents may be gripped by desperation and seek out any therapeutic alternative. They may also exhibit denial about the incurability of their child’s disease. Other parents may suffer guilt about their relationship with the child and compensate for previous inadequacies by insisting on aggressive treatment. These factors may skew deliberation about whether participation in a phase I trial will serve their child’s interests. For example, they may give too much weight to the possibility of a meaningful remission or discount the comparative merits of pursuing palliative care measures. Thus, the decision may not reflect their goals for protecting the child’s welfare. Psychosocial constraints affecting parents and children can exercise a powerful influence on their decision making. One strategy for mitigating this impact is to insure that they clearly understand the potential benefits and harms of participation in the phase I trial, as well as the comparative features of palliative care. Another strategy is for caregivers to facilitate the family’s resolution of affective constraints. For example, it may be possible to elicit any reservations the child may have about participation and to convey these reservations to the parents. Similarly, if the parents exhibit denial about the incurability of their child’s disease, further dialogue may help to reduce unrealistic hopes for the phase I therapy. Such interventions may encourage a decision that reflects the concerns most important to the family. Thus, administration of chemotherapy in a phase I pediatric oncology trial is properly considered a therapeutic intervention. Whether the best interests of the child will be served depends on the relative importance attached by child and parents to the possible consequences of the intervention. Powerful affective factors confront caregivers with a complex challenge in assuring that the family’s decision genuinely reflects their underlying values and goals related to the care of the child.
D
ESPITE TREMENDOUS STRIDES in the development of chemotherapy for childhood cancer, current failure rates continue to spur the search for drugs with greater efficacy and safety. A drug showing promise in laboratory and animal studies is first administered to humans in a phase 1 clinical trial. The primary objectives of the trial are to determine the maximum tolerable dose of the drug and to develop a preliminary profile of its toxicities. The search for the maximum tolerated dose reflects the assumption that cancer chemotherapy is most likely to be effective at a toxic but tolerable dose. The design of a phase 1trial involves an escalating dose scheme in which each successive group of subjects is treated at a higher dose. The first group receives a dose unlikely to be either toxic or beneficial, and the dose level for each subsequent group is increased until a maximum tolerated dose is identified. Subjects are incurable patients whose cancer has proven refractory to more established forms of treatment, but whose performance status is still sufficiently strong to undergo additional chemotherapy. lnformation regarding the maximum tolerated dose and prominent toxicities is used to define the appropriate dosing for subsequent trials of the drug’s efficacy. Phase 1 trials of a new drug are usually initiated in adult cancer patients. They must be repeated separately for children because drug pharmacokinetics may differ in pediatric subjects. For example, the maximum tolerated dose is usually higher in children than adults. In ad-
From the Department of Human Values and Ethics, College of Medicine, University of Tennessee, Memphis, TN. Address reprint requests to Terrence F. Ackerman, PhD, Department of Human Values and Ethics, 956 Court Ave, 8324 Coleman Bldg, College of Medicine, University of Tennessee, Memphis, TN 38163. 0 1995 by Association of Pediatric Oncology Nurses. 1043-4542/95/l 203-0010$03.00/0
Journal
of Pediatric
Oncology
Nursing,
dition, severe and dose-limiting toxicities are sometimes different for adult and pediatric patients. These disparities prevent formulation of an appropriate dose for child cancer patients based on adult phase 1 studies. Despite the necessity of phase 1 trials in children, ethical issues have persisted regarding their conduct. A basic question is whether the administration of chemotherapy in a phase 1trial can be undertaken with “therapeutic intent.” Because the toxicities of the drug may expose children to serious risk of harm, its use cannot be morally justified if considered a nontherapeutic procedure. Moreover, even if administration of chemotherapy in a phase 1 trial is properly regarded as therapeutic, its moral acceptability depends on whether it promotes the best interests of subjects. In addition, involvement of children in a phase I study requires that investigators be able to secure the understanding and free agreement of the parents and of the children who are capable of assent. Some critics have doubted that any of these conditions can be satisfied, and their concerns require serious examination. The first issue is whether administration of phase 1 chemotherapy to pediatric subjects should be considered a therapeutic research intervention. Commentators who reject this position point out that the purpose of a phase 1 trial is to explore the tolerable limit of the drug’s toxicities and is not to evaluate its efficacy in achieving remission. They claim that the escalating dose scheme, starting with a conservative dose unlikely to cause serious toxicity, virtually assures that early subjects will not achieve remission. Moreover, they assert that there is no reasonable expectation of therapeutic success, given that retrospective analysis of pediatric phase I trials reveals a response rate (complete and partial) under 6%. However, there are good reasons for viewing Vol 12, No 3 (July),
1995: pp 143-145
143
144
Terrence
administration of chemotherapy in a phase I trial as a therapeutic intervention. Although the objective of the study is to establish a maximum tolerable dose, this does not preclude the additional goal of providing therapeutic benefit to subjects. Moreover, when subjects suffer from progressive disease refractory to more established forms of treatment, any chance for further remission might be viewed as offering reasonable expectation of success. Finally, there are potential therapeutic benefits other than disease remission, including stabilization of disease progression, reduction in pain symptomatology and maintenance of hope. If administration of phase I chemotherapy is properly considered a therapeutic intervention, two important criteria (encoded in the federal regulations on pediatric research) must be satisfied to establish that it promotes the best interests of subjects. One is that the risks to subjects are justified by the intended benefits. The other is that the risk/benefit ratio of chemotherapy is as favorable as that of any alternative strategy for managing the disease. In weighing the risks and benefits, several considerations are pertinent. The potential benefits include the slight chance of disease remission or stabilization, maintenance of hope, reduction of pain or discomfort and, for some older children, altruistic satisfaction of contributing to the development of new treatments. The risks of harm include lethal complications of the chemotherapy, which occur in somewhat less than 3% of subjects in pediatric phase I trials. More common, nonlethal complications include infection, bleeding, impaired renal and hepatic function, and nausea and vomiting. There is also the added pain and discomfort from diagnostic procedures used to monitor drug toxicities. Finally, additional time in the hospital may be necessary due to side-effects of the drug. The risk/benefit ratio of participating in the phase I trial must also be compared with the advantages and disadvantages of managing the child’s illness through the provision of palliative care only. Although the latter alternative precludes the opportunity for any further remission, it might possess several advantages. The child would be spared any suffering associated with the provision of additional chemotherapy. The
E Ackerman
child would avoid the pain and discomfort involved in the diagnostic procedures used to monitor drug toxicities. In addition, suspension of further chemotherapy might allow more time at home before the child’s death. These advantages would be conjoined with care focusing on relief of the symptoms and complications resulting from disease progression. Determination of whether the risks of participating in a phase I trial are justified by the anticipated benefits, and whether the risk/benefit profile compares favorably with palliative care, cannot be settled merely by enumerating the factors cited above. These judgments require assignment of a relative weight or importance to these considerations. For example, the risk/ benefit assessment of receiving phase I therapy depends on whether the slight chance of further remission is assigned greater weight than the possible discomforts and dangers associated with treatment toxicities. Similarly, the comparative advantages of chemotherapy or palliative care depend partly on the relative importance assigned to brief remission of disease versus the opportunity to spend more time at home. These judgments can only be made relative to certain values and goals. Because the consequences of the decision must be borne by the child and parents, it is their values and goals that should determine the relative weight of these factors. The judgment of what serves the child’s interests will depend on drawing out a clear understanding of the values and goals important to the family at this point in the child’s illness. This conclusion suggests that the appropriateness of the decision to enter a child in a phase I trial will depend on the adequacy of the informed consent process. Assurance that the decision reflects the values and goals of the family requires that it be both fully informed and free from serious affective constraints. An adequately informed decision involves the provision of key items of information. The family must understand the purpose of the phase I trial and the very low probability of further remission of the child’s disease. The number and types of monitoring procedures required must be clearly delineated. Uncertainties about the toxicity of the dose level used must be explained. Perhaps most importantly, there must be a candid and complete discussion of the merits and disadvan-
Phase
tages of participating in the trial compared with managing the child’s disease with palliative care measures. These considerations must be discussed within the framework of the basic understanding that the child’s cancer cannot be cured and that even an extended remission is no longer a realistic prospect. Adequately informed families may choose to participate in a phase 1 trial and this decision may genuinely reflect their values and goals. They may feel that it is not yet time to give up hope of further remission. The child may feel reasonably well and be willing to accept the rigors of additional chemotherapy. Both parents and child may find satisfaction in contributing to the development of new treatment. For many families, participation will be the most suitable way to act on the considerations most significant to them. Nevertheless, there are troubling affective constraints that can impair the decision making of child and family. By affective constraints, I mean psychosocial factors that skew the ability to make a decision that genuinely reflects their values and goals. In the case of preadolescent children, the affective constraints involve their limited capacity for independent decision making. Studies in developmental psychology clearly show that preadolescent children have a weak sense of control over interventions in their lives and a strong need to conform to adult expectations. Different affective constraints are encountered with adolescents. They may feel guilty about “failing” their parents by having an incurable disease, and are often highly concerned to do what will please their parents or ease their burden of suffering. They may believe that their parents’ ability to deal with their illness will be enhanced if another therapeutic intervention is attempted. An important implication of these affective factors is that children who are weary of treatment may be inclined to not articulate their reservations if parents and caregivers are strongly in favor of their participation in the phase I trial. Thus, their participation may not reflect their own values and goals. A different set of affective constraints may im-
I Trials
145
pinge on the decision making of parents. As their child’s disease proves refractory to more established forms of treatment, parents may be gripped by desperation and seek out any therapeutic alternative. They may also exhibit denial about the incurability of their child’s disease. Other parents may suffer guilt about their relationship with the child and compensate for previous inadequacies by insisting on aggressive treatment. These factors may skew deliberation about whether participation in a phase I trial will serve their child’s interests. For example, they may give too much weight to the possibility of a meaningful remission or discount the comparative merits of pursuing palliative care measures. Thus, the decision may not reflect their goals for protecting the child’s welfare. Psychosocial constraints affecting parents and children can exercise a powerful influence on their decision making. One strategy for mitigating this impact is to insure that they clearly understand the potential benefits and harms of participation in the phase I trial, as well as the comparative features of palliative care. Another strategy is for caregivers to facilitate the family’s resolution of affective constraints. For example, it may be possible to elicit any reservations the child may have about participation and to convey these reservations to the parents. Similarly, if the parents exhibit denial about the incurability of their child’s disease, further dialogue may help to reduce unrealistic hopes for the phase I therapy. Such interventions may encourage a decision that reflects the concerns most important to the family. Thus, administration of chemotherapy in a phase I pediatric oncology trial is properly considered a therapeutic intervention. Whether the best interests of the child will be served depends on the relative importance attached by child and parents to the possible consequences of the intervention. Powerful affective factors confront caregivers with a complex challenge in assuring that the family’s decision genuinely reflects their underlying values and goals related to the care of the child.