As advances in medicine and technology improve the survival of children with cancer, attention to health-related quality of life and progress in symptom management has not kept pace with advances in disease-directed therapies. This disparity creates a population of children who are living with cancer but who suffer from inadequate symptom control. The paucity of systematic research in symptom management leads to a lack of evidence or standards on which to base interventions, which leads, at least in part, to suboptimal supportive care.

Fatigue is frequently reported to be the most incapacitating of symptoms, preventing children from partaking in meaningful life experiences, thereby impairing quality of life. In a cross-sectional retrospective survey of parents of children who died of cancer, at Dana Farber Cancer Institute/ Children’s Hospital Boston ( DFCI/ CHB) led by Dr. Joanne Wolfe, 96% of children experienced some degree of fatigue, with 49% of children suffering significantly from it.1 Through further analysis of these data, with an additional cohort of parents from Children’s Hospital of St Paul and Minneapolis, we have found that suffering from fatigue is associated with suffering from pain, dyspnea, anorexia, nausea/vomiting, anxiety, sadness, or fear (P<0.05) and with side effects from pain or dyspnea treatment (P<0.05).2

Increased attention to and treatment for fatigue is needed

Despite the extremely high prevalence of fatigue we found that only 52% of children with fatigue had it documented as a symptom in their medical records. Furthermore, among children with fatigue, 17/129 (13%) received fatigue-directed treatment, which was successful in only 3/12 (25%).2 This cohort predated the creation of a pediatric palliative care team at our institution. Since the inception of this service, parents of children who died from cancer report less suffering from symptoms including pain, dyspnea, anxiety and sadness.3 Even with the introduction of a palliative care service, however, suffering from fatigue has not diminished, highlighting the need for increased attention to fatigue. 3

Methylphenidate is an attractive intervention for fatigue

Despite its significant impact, cancer-related fatigue remains profoundly under treated, largely due to a lack of proven interventions for fatigue. Several studies have demonstrated that methylphenidate (MPH) improves fatigue as well as mood, pain and cognition in adults with cancer regardless of the exact cause of fatigue.4-7 Our collaborator, Dr. Charles Berde, has reported positive experience with a small open-label case series of children with advanced cancer receiving stimulants for opioid-induced sedation.8 Outside of this study there are no published reports of treatment of fatigue in children with cancer, nor any well-established therapies for it in this population. MPH may ameliorate fatigue in children with serious illness, but a study aiming to systematically evaluate a fatigue-directed intervention in children is needed.

Symptom-related research in children with cancer and the N-of-1 Trial

High quality symptom-related research in pediatrics faces many potential barriers including rarity of disease, developmental concerns, ethical issues, low subject enrollment rates, attrition, and the highly emotionally charged nature of caring for children with life-threatening illness.9 Novel study designs, such as the N-of-1 trial (N1T), have been well-described by the Institute of Medicine and can potentially circumvent some of these barriers. 10 An N1T is a randomized controlled trial (RCT) within an individual patient that allows key stakeholders, patients and families to participate directly in balancing therapeutic benefits and adverse effects in collaboration with the care team. Combining N1T results assesses efficacy and adverse effects for the entire group with a sample size smaller than that required by a traditional parallel design RCT.11-14

Through opportunities to receive the potentially active agent and by immediate determination of whether the intervention benefited the participant, the N1T directly benefits all participants, thereby avoiding participant, parent and clinician concerns inherent in other RCT designs. For this reason the N1T design may be particularly applicable to research in children, particularly those with serious illness such as cancer. While the non-modifiable realities of research in pediatrics, such as patient attrition due to symptoms, disease progression or death may be unavoidable, studies that minimize patient and family burden while maximizing benefit may enhance opportunities for productive research.

Aims

1a) To evaluate the feasibility of the N1T in evaluating an intervention for children with cancer.

1b) To evaluate the ability of the N1T to assess efficacy of an intervention for children with cancer.

2) To evaluate the efficacy and side effects of MPH for fatigue in children with cancer.



Methods

Children 7-21 years meeting eligibility criteria will be enrolled. Treatment will be composed of 3 treatment pairs, with each pair consisting of 3 days of MPH and 3 days of placebo. With a focus on the child’s experience during the treatment phase, flexibility in the study design and dose modification has been incorporated. Participants, their parents, and the study team will assess the child’s response to MPH together and determine if dose modifications are needed, and whether MPH should be continued after study completion. This flexibility will maximize a participant’s opportunity to work with the study team to derive benefit from MPH and to determine optimal dosing, while preserving a study structure that will generate quality data for analysis. Such emphasis on joint decision-making, based on the individual child’s experience, is a unique feature of this N1T, and is not routinely part of most clinical trials which do not include an individual’s benefit as a priority.

Potential Impact

The N1T is a family-centered study method that encourages active participation in the study. Furthermore, it directly provides them with information that may facilitate shared decision-making with the child’s care team. By combining individual results, and demonstrating utility of this innovative method, this study will inform conduct of future studies to improve quality of life and symptoms in children with complex, disabling illness. Finally, it will contribute to the management of a common and highly distressing symptom experienced by children with serious illness.

Support from the Hyundai Scholar Program would provide funding essential for successful completion of this project. Funds would be used for salary support and research materials during the term of the award. The preliminary data generated will be used to seek additional funding for a larger, multicenter trial.

References

1. Wolfe J, Grier H, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. NEJM. 2000; 342(5):326-333.

2. Ullrich C, Dussel V, Hilden J. et al. Understanding Fatigue in Children with Advanced Cancer. J. Pain Symptom Manage. (in press).

3. Wolfe J, Hammel JF, Edwards KE, et al. Easing of suffering in children with cancer at the end of life: is care changing? J Clin Oncol. 2008; 26(10):1717-23.

4. Bruera E, Chadwick S, Brenneis C, Hanson J, MacDonald R. Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep. 1987; 71(1):67-70.

5. Bruera, E, Fainsinger, MacEachern T, Hanson J. The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report. Pain. 1992; 50(1):75-77.

6. Bruera E, Miller M, Macmillan K, Kuehn N. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain. 1992; 48(2):163-166.

7. Bruera E, Driver L, Barnes E, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol. 2003; 21(23):4439-4443.

8. Yee J and Berde C. Dextroamphetamine or methylphenidate as adjuvants to opioid analgesia for adolescents with cancer. J Pain Symptom Manage. 1994; 9(2):122-125.

9. Davies B, Steele R, Stajduhar K, Bruce A. Research in Pediatric Palliative. In: Portenoy R and Bruera E, eds. Issues in Palliative Care Research. Oxford: Oxford University Press, 2003.

10. Institute of Medicine Committee on Strategies for Small-Number-Participant Clinical Research Trials, Board on Health Sciences Policy. Small Clinical Trials: Issues and Challenges. Washington, D.C.: National Academies Press, 2001.

11. Guyatt G, Sackett D, Taylor W et al. Determining optimal therapy-randomized trials in individual patients. N Engl J Med. 1986; 314(14):889-892.

12. Guyatt G, Keller J, Jaeschke R, et al. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med. 1990; 1212(4):293-299.

13. Guyatt G, Rennie D, eds. User’s Guides to the Medical Literature: A manual for evidence-based clinical practice. Chicago: AMA Press, 2002.

14. Sung L, Feldman B. N-of-1 Trials: Innovative methods to evaluate complementary and alternative medicines in pediatric cancer. J Pediatr Hematol Oncol. 2006; 28(4):263-266.