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Journal of Clinical Oncology, Vol 18, Issue 9 (May), 2000: 1900-1905
© 2000 American Society for Clinical Oncology

Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group

By E. J. Estlin, S. Cotterill, C. B. Pratt, A. D. J. Pearson, M. Bernstein

From the Department of Paediatric Oncology, Royal Hospital for Sick Children, Bristol, and Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; St Jude Children’s Research Hospital, Memphis, TN; and Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

Address reprint requests to E.J. Estlin, MD, PhD, Department of Paediatric Oncology, Royal Hospital for Sick Children, St Michael’s Hill, Bristol BS2 8BJ, United Kingdom; email e.j.estlin{at}bristol.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To identify areas of concern regarding the conduct of phase I trials, the perceived expectations and motivations of the parents of children entered, the expectations of toxicity and benefit, and the ethical concerns of pediatric hematologists and oncologists in the United Kingdom and North America.

METHODS: A survey instrument consisting of 19 open- and closed-ended questions was sent to United Kingdom Children’s Cancer Study Group (UKCCSG)– and Pediatric Oncology Group (POG)–affiliated pediatricians.

RESULTS: Fifty-three UKCCSG- and 78 POG-affiliated pediatricians responded. Thirty-two UKCCSG and 51 POG respondents had previously entered at least one child into a phase I study. Overall, respondents believed that parents entered their children for medical benefit, altruism, and hope of cure. Although many respondents believed that children could benefit from medical improvement, feelings of altruism, and maintenance of hope, the chance of cure or complete remission was thought to be small. Similarly, parents were thought to potentially benefit through altruism and maintenance of hope. Whereas 83% of UKCCSG respondents indicated that phase I trials were associated with ethical difficulties, this was a concern for 48% of POG respondents. The main ethical concerns of respondents were risk of toxicity, consent of the child, unrealistic hope, and coercion.

CONCLUSION: The respondents in this survey expressed mainly ethical concerns regarding the conduct of phase I trials and had realistic expectations of the potential for toxicity and benefit for those children who participate in these studies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PHASE I TRIALS ARE needed for both the rational introduction of new therapies into pediatric oncology practice and the evaluation of combinations of new and established agents. The aims of and methodology for phase I trials in pediatric oncology have been the subject of recent reviews.1,2 Phase I trials are designed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics and pharmacodynamics of new agents by a dose-escalation method.1,2 A secondary, although important, aim of phase I trials is to seek preliminary evidence of efficacy of the new agents; however, phase II trials are needed for the formal testing of the effectiveness of a new agent or combination.

Because the eligibility criteria for entry of children into phase I trials usually demand that all recognized conventional treatments have failed, this may create difficulty in reconciling the natural desire of parents and children themselves to proceed with treatment at any cost and the need to provide good-quality palliative care to children who will in most cases die. However, the rational introduction of new therapies in pediatric oncology can be achieved only by means of a phase I study.

The perceptions of physicians, institutional review board chairpersons,3 and patients4 involved in adult phase I studies were reported recently. Although the ethical and legal issues regarding the therapy of children with investigational anticancer drugs have been discussed by several authors,5,6 there have been no published surveys of the perceptions of pediatric hematologists and oncologists regarding phase I trials in children with cancer. The aim of this present survey was to identify areas of concern regarding the conduct of phase I trials, the perceived expectations and motivations of the parents of children entered, the expectations of toxicity and benefit, and the ethical concerns of pediatric hematologists and oncologists in the United Kingdom and North America. In addition, the expectations of physicians regarding the toxicity and benefit associated with phase I trials in pediatric oncology were compared with the findings of a review of 28 recently published single-agent phase I studies.7-35


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We designed a survey instrument that consisted of 19 questions. (For a copy of the instrument, please contact Dr. Estlin.) In the United Kingdom, all specialist pediatric hematologists and oncologists are members of the United Kingdom Children’s Cancer Study Group (UKCCSG). A list of specialists who would be in a position to enter or refer a patient for a phase I trial was obtained from the UKCCSG Data Centre, Department of Epidemiology and Public Health, University of Leicester, Leicester, United Kingdom. Seventy persons were identified from this list, and the questionnaire was mailed to them in May 1996. The response rate from the first mailing was 33%, rising to 75% (53 respondents) after a second reminder. The 53 respondents represented 22 different children’s cancer treatment centres in the United Kingdom. In North America, pediatric hematologists and oncologists with attending (or equivalent) status at 110 Pediatric Oncology Group (POG)–affiliated institutions were identified (n = 435) for the purposes of this questionnaire, and the response rate was 18% (78 respondents).

For data analysis, the responders were divided into two groups: those who had entered at least one patient onto a phase I study (group A) and those who had never entered a patient onto a phase I study (group B). The responses for each question were analyzed both as the aggregated responses for all respondents and as a comparison between groups A and B. Fisher’s exact test was used to examine for significant differences between the two groups of respondents.

To compare the perceptions of pediatricians regarding the toxicity associated with and benefit derived from the participation of children in phase I trials, a survey of 28 phase I trials that were published between 1989 and 1998 in peer-reviewed journals was undertaken. The aim of this survey was to identify the total number of children entered onto these studies and to ascertain the number of children who satisfied the criteria for toxicity evaluation, the number of children treated within 20% of the MTD, the number who experienced DLT, the number of toxic deaths, and the number of children who benefited in terms of stable disease, partial response, or complete remission.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Thirty-two respondents from the United Kingdom and 51 respondents from North America had previously entered a patient onto a phase I trial (group A). Twenty-one and 27 respondents from the United Kingdom and North America, respectively, had not previously entered a patient onto a phase I study (group B).

Respondents’ Concepts of the Purpose of Phase I Trials
For the internationally accepted aims of phase I studies in pediatric oncology, namely, the definition of DLT, MTD, pharmacokinetics, and efficacy, 28% of group A identified >= three of these aims, compared with 15% of group B (P = .06). The majority of respondents correctly identified toxicity/DLT and the MTD as the principal aims of phase I studies.

Respondents’ Perceptions of the Difficulties Associated With Phase I Trials
On open-ended questioning, respondents expressed mainly specific ethical concerns regarding phase I trials, ie, informed consent, as well as stated ethical concerns in general (Table 1).


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  		Table 1. Difficulties Associated With Phase I Studies (responses to an open-ended question)
 
Reasons Pediatricians Enter Children Onto Phase I Studies
Pediatricians from group A were more likely to specify relapsed disease with no other treatment option as a reason for entering children onto phase I studies than those from group B (P = .02). Other reasons volunteered on open-ended questioning are listed in Table 2. Whereas 13 of 53 UKCCSG respondents specified "discuss with family," this was identified in only three of 78 respondents from the POG (P = .002). However, 14 of 78 POG respondents specified that a child should have a life expectancy sufficient to allow the collection of toxicity data, compared with two of 53 UKCCSG respondents (P = .02).


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  		Table 2. Reasons That Pediatricians Would Consider Entering a Patient Into a Phase I Study (responses to an open-ended question)
 
Pediatricians’ Perceptions of Reasons Why Parents Allow Entry of Their Children Onto a Phase I Study
The responses of pediatricians from group A and group B to open-ended questions were similar, with medical benefit, altruism, and hope of cure being identified as reasons parents agree to enter their children onto a phase I study (Table 3). When offered potential reasons that might influence parents’ decisions to enter their child onto a phase I study, pediatricians perceived the most important reasons to be the maintenance of parental hope and the possibility of medical benefit or cure. Altruism and pressure from family members or medical staff were thought to be less important (Fig 1). There were no major differences between the responses from group A and group B or between UKCCSG and POG pediatricians.


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  		Table 3. Pediatrician’s Perceptions of Reasons Why Parents Agree for Their Children to Enter a Phase I Study (responses to an open-ended question)
 


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  		Fig 1. Pediatricians’ perceptions of reasons why parents allow their children to enter a phase I study (responses to a closed-ended question). For each reply, respondents were asked to rank each reason in order of importance from 1 to 7, with 1 being the most important.

 
Pediatricians’ Perceptions of Potential Benefits to Children Participating in Phase I Trials
The respondents believed that children could receive both medical and psychologic benefit by participating in phase I trials. However, 15% of respondents thought that children would receive no benefit from their participation (Table 4). On closed-ended questioning, respondents thought that whereas children had only a small or very small chance of cure or complete remission, they were more likely to achieve a partial response and/or significant palliation as a result of entering a phase I trial.


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  		Table 4. Pediatricians’ Perceptions of Potential Benefit for Children Who Participate in Phase I Trials (responses to an open-ended question)
 
Pediatricians’ Perceptions of Potential Benefits to the Parents of Children Participating in Phase I Trials
The responses obtained on open-ended questioning were similar to the perceptions of the benefits to children. Overall, 50%, 47%, and 40% of respondents thought that parents would benefit through altruism, the maintenance of their hope, and the potential for medical benefit for their child, respectively. Moreover, whereas 20 of 131 respondents indicated that there was no benefit to the children taking part in phase I trials (open-ended questioning), three of 131 indicated that there was no benefit for parents (P < .001).

Pediatricians’ Perceptions of Potential Disadvantages for Children Participating in Phase I Trials
The majority (71%) of respondents expected a child to have at least a 50% chance of experiencing toxicity by participating in a phase I study. However, the risk of life-threatening toxicity was thought to be small (40%) or very small (55%). Similarly, the risk of toxic death was thought to be small (16%) or very small (82%). In addition to the risk of toxicity, other ethical considerations were indicated by the respondents (Table 5). However, UKCCSG respondents were more likely than POG respondents to indicate that they considered phase I studies to be associated with ethical difficulties (83% v 48%; P < .001).


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  		Table 5. Pediatricians perceptions’ of the Ethical Considerations Associated With Phase I Trials (responses to an open-ended question)
 
Moreover, certain differences between POG and UKCCSG respondents were found when ethical difficulties were considered by means of a closed-ended question. Whereas 28% of UKCCSG respondents placed "undertreatment" in the bottom two categories of importance, this was less of a concern for 49% of POG respondents (P = .02). Similarly, more UKCCSG respondents than POG respondents placed the consent of children (83% v 64%; P = .01), children’s hope (68% v 46%; P = .01), and parental hope (70% v 53%; P = .04) in the top two categories of importance.

Pediatricians Perceptions of Other Issues in Relation to Phase I Trials
Although 13% of respondents believed that the families of children entering phase I studies did not require an increased level of support (12% of respondents were uncertain), 75% of respondents believed that an increased level of support was necessary, and all members of the multidisciplinary team were important in this respect.

Survey of Single-Agent Phase I Studies From 1989 to 1998
A total of 710 children/young adults had been entered onto the 28 phase I studies identified.7-35 Overall, 90% (n = 636) of patients entered were eligible for toxicity evaluation, and DLT was observed in 21% of cases (n = 147). However, death attributable to drug-related toxicity was found in only four cases (0.56%). Fifty-nine percent (n = 422) received therapy within ± 20% of the MTD, and complete remissions, partial responses, and stable disease were identified in 2% (n = 13), 8% (n = 56), and 10% (n = 72) of cases, respectively. Pharmacokinetic analyses were performed in 16 of the studies.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This survey has ascertained the perceptions of pediatric oncologists affiliated with the UKCCSG and POG in relation to the nature of phase I trials. In this survey, the majority of respondents correctly identified the definition of DLT and the MTD as the purpose of phase I trials. Moreover, pediatricians with experience of entering children onto phase I studies were more likely to identify the aims of phase I studies in terms of MTD, DLT, pharmacokinetics, and efficacy, but less than 30% of respondents identified all of these elements. Many areas of difficulty associated with phase I trials were identified by the respondents, including ethical concerns, invasiveness, hospitalization, level of documentation required, and access to these trials. The majority of respondents identified that children with relapsed or refractory disease with no other treatment options would be eligible for entry onto a phase I study.

The pediatricians in our survey volunteered the potential for medical benefit, altruism, and psychological factors such as maintaining hope as the main reasons parents enter their children onto a phase I study. This perception is similar to that of oncologists involved in the care of adult patients, of whom 75% and 94% of respondents believed that adults enrolled onto phase I studies for psychologic benefit and the potential of medical benefit, respectively.3 In the present study, however, pediatricians believed that parents may be influenced by altruism when entering their children onto phase I studies. In contrast, altruism was not volunteered in a study of adult patients participating in phase I studies and was identified as a reason to participate in only one third of adults on closed-ended questioning.36

When considering the potential benefits for children who participate in phase I studies, the majority of respondents believed that children could potentially benefit medically, and more than 30% identified psychologic benefit, such as hope and altruism. These perceptions correlated well with those obtained via closed-ended questioning. The expectations of pediatricians in the present study with regard to potential benefit afforded by phase I trials are largely in keeping with the reported response rate of 5.9% for pediatric phase I studies.37 Moreover, in our study of response rates identified from 28 single-agent phase I studies published between 1989 and 1998, an overall objective response rate of 10% was found, with the majority of these being partial responses to therapy. Therefore, the pediatricians in this survey possibly overestimated the potential for medical benefit or palliation, although the true incidence of stable disease, improvement in palliation, and psychologic benefit is not generally reported in published trials. Indeed, the tendency for oncologists involved in adult phase I studies to overestimate the potential for therapeutic benefit has also been reported.36 Altruism and psychologic factors were identified as potential benefits for parents in this present survey.

Although the majority of respondents expected a child to have at least a 50% chance of experiencing toxicity, the risk of death due to drug-related toxicity was thought to be very small. This is in agreement with the findings of Furman et al,37 who reported a 2.4% toxic death rate. Indeed, in the present survey of more recently published single-agent phase I trials, although 21% of children experienced DLT, the toxic death rate was 0.56%.

In addition to the risk of toxicity, many pediatricians volunteered other ethical considerations, such as the consent of children and unrealistic hope, as areas of concern. Indeed, the ethics of phase I trials have been addressed by several authors in the past. For example, Lipsett38 considered that although therapeutic intent must always be the primary justification for entering a patient onto a phase I trial, such studies, which are performed with a particularly vulnerable patient population, may represent the killing of the individual for the benefit of society. Moreover, Janofsky and Starfield39 considered clinical research to be an essential tool in the accumulation of knowledge in pediatrics and other branches of medicine, without which children become the "therapeutic orphans of the medical community." However, whereas more than 80% of all UKCCSG respondents indicated that phase I trials were associated with ethical difficulties, this concern was expressed by 48% of those with POG affiliation. A similar level of ethical concern was expressed in a survey of oncologists involved with adult phase I trials in North America: 55% of respondents thought that phase I trials were associated with ethical difficulties.3 Finally, 75% of respondents recognized the importance of an increased level of multidisciplinary support for the families of children who participate in phase I trials.

In conclusion, the present survey indicates that pediatricians affiliated with the UKCCSG and POG have a good understanding of the aims of phase I trials and have realistic expectations in terms of the risk of toxicity and the chance of medical benefit. Many pediatricians identified several ethical difficulties associated with the conduct of phase I trials in children. Thus, further studies are needed to examine more closely the ethical issues involved in phase I trials in pediatric oncology, including the process of informed consent and the expectations of the parents and children who participate.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Smith M, Bernstein M, Bleyer WA, et al: Conduct of phase I trials in children with cancer. J Clin Oncol 16:966-978, 1998[Abstract]

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3. Kodish E, Stocking C, Ratain MJ, et al: Ethical issues in phase I oncology research: A comparison of investigators and institutional review board chairpersons. Clin Oncol 10:1810-1816, 1992

4. Penman DT, Holland JC, Bahna GF, et al: Informed consent for investigational chemotherapy: Patients and physicians perceptions. J Clin Oncol 2:849-855, 1984[Abstract]

5. Truman JT, Brant J: Ethical and legal issues in the treatment of children with cancer. Pediatr Hematol Oncol 6:313-317, 1984

6. Pratt CB: The conduct of phase I-II clinical trials in children with cancer. Pediatr Oncol 19:304-309, 1991

7. Mahmoud HH, Pui CH, Kennedy W, et al: Phase I study of recombinant human interferon gamma in children with relapsed leukaemia. Leukemia 6:1181-1184, 1992[Medline]

8. Adamson PC, Balis FM, Miser J, et al: Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a low-dose, intermittent schedule. Cancer Res 52:521-524, 1992[Abstract/Free Full Text]

9. Weisdorf DJ, Anderson PM, Blazar BR, et al: Interleukin 2 immediately after autologous bone marrow transplantation for acute lymphoblastic leukaemia: A phase I study. Transplantation 55:61-66, 1993[Medline]

10. Heideman RL, Gillespie A, Ford H, et al: Phase I trial and pharmacokinetic evaluation of fazarabine in children. Res 49:5213-5216, 1989

11. Avramis VI, Champagne J, Sato J, et al: Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. Cancer Res 50:7226-7231, 1990[Abstract/Free Full Text]

12. Patel R, Newman EM, Villacorte DG, et al: Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: A report from the Children’s Cancer Study Group. Cancer Res 51:4871-4875, 1991[Abstract/Free Full Text]

13. Adamson PC, Balis FM, Miser J, et al: Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule. Cancer Res 50:4464-4467, 1990[Abstract/Free Full Text]

14. Roper M, Smith MA, Sondel PM, et al: A phase I study of interleukin-2 in children with cancer. Oncol 14:305-311, 1992

15. Allen J, Packer R, Bleyer A, et al: Recombinant interferon beta: A phase I-II trial in children with recurrent brain tumours. J Clin Oncol 9:783-788, 1991[Abstract]

16. Green DM, Krischer JP, Bell B, et al: Phase I study of a 120-hour continuous intravenous infusion of 5-fluorouracil in pediatric patients with recurrent solid tumours: A Pediatric Oncology Group study. Med Pediatr Oncol 18:321-324, 1990[Medline]

17. Santana VM, Mirro J, Harwood FC, et al: A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 9:416-422, 1991[Abstract]

18. Smith MA, Adamson PC, Balis FM, et al: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer. J Clin Oncol 10:1666-1673, 1992[Abstract/Free Full Text]

19. Lashford LS, Lewis IJ, Fielding SL, et al: Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: A United Kingdom Children’s Cancer Study Group investigation. J Clin Oncol 10:1889-1896, 1992[Abstract]

20. Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032-1036, 1993[Abstract/Free Full Text]

21. Furman WL, Strother D, McClain K, et al: Phase I clinical trial of recombinant human tumour necrosis factor in children with refractory solid tumours: A Pediatric Oncology Group study. J Clin Oncol 11:2205-2210, 1993[Abstract/Free Full Text]

22. Adamson PC, Balis FM, Belasco JE, et al: A phase I trial of amifostine (WR-2721) and melphalan in children with refractory cancer. Cancer Res 55:4069-4072, 1995[Abstract/Free Full Text]

23. Furman WL, Baker SD, Pratt CB, et al: Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia. J Clin Oncol 14:1504-1511, 1996[Abstract/Free Full Text]

24. Ettinger LJ, Krailo MD, Gaynon PS, et al: A phase I study of carboplatin in children with acute leukaemia in bone marrow relapse. Cancer 72:917-922, 1993[Medline]

25. Pratt CB, Meyer WH, Douglass EC, et al: A phase I study of ifosfamide with mesna given daily for 3 consecutive days to children with malignant solid tumours. Cancer 71:3661-3665, 1993[Medline]

26. Pratt CB, Douglass EC, Kovnar EH, et al: A phase I study of ifosfamide given on alternate days to treat children with brain tumours. Cancer 71:3666-3669, 1993[Medline]

27. Hurwitz CA, Relling MV, Weitman SD, et al: Phase I trial of paclitaxel in children with refractory solid tumours: A Pediatric Oncology Group study. J Clin Oncol 11:2324-2329, 1993[Abstract/Free Full Text]

28. Marina NM, Rodman J, Shema SJ, et al: Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumours. J Clin Oncol 11:554-560, 1993[Abstract/Free Full Text]

29. Mathew P, Ribero RC, Sonnichsen D, et al: Phase I study of oral etoposide in children with refractory solid tumours. Oncol 12:1452-1457, 1994

30. Kitchen BJ, Bals FM, Poplack DG, et al: A pediatric phase I trial and pharmacokinetic study of thioguanine administered by continuous infusion. Clin Cancer Res 3:713-717, 1997[Abstract]

31. Blaney SM, Seibel NL, O’Brien M, et al: Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumours: A collaborative pediatric branch, National Cancer Institute and Children’s Cancer Group trial. J Clin Oncol 15:1538-1543, 1997[Abstract]

32. Bernstein ML, Whitehead VM, Grier H, et al: A phase I trial of fazarabine in refractory pediatric solid tumours: A Pediatric Oncology Group study. Invest New Drugs 11:309-312, 1993[Medline]

33. Baruchel S, Bernstein M, Whitehead VM, et al: A phase I study of acivicin in refractory pediatric solid tumors. Invest New Drugs 13:211-216, 1995[Medline]

34. Pratt CB, Bowman LC, Marina N, et al: A phase I study of sulofenur in refractory pediatric malignant solid tumours. Drugs 13:63-66, 1995

35. Estlin EJ, Lashford L, Ablett S, et al: Phase I study of temozolomide in paediatric patients with advanced cancer. Cancer 78:652-661, 1998

36. Daugherty C, Ratain MJ, Grochowski E, et al: Perceptions of cancer patients and their physicians in phase I trials. J Clin Oncol 13:1062-1072, 1995[Abstract]

37. Furman WL, Pratt CB, Rivera GK: Mortality in pediatric phase I clinical trials. J Natl Cancer Inst 81:1193-1194, 1989[Free Full Text]

38. Lipsett MB: On the nature and ethics of phase I clinical trials of cancer chemotherapies. JAMA 248:941, 1982[Medline]

39. Janofsky J, Starfield B: Assessment of risk in research on children. J Pediatr 98:842-846, 1981[Medline]

Submitted June 21, 1999; accepted January 10, 2000.




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