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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2073-2078 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.8506 Patient-Controlled Methylphenidate for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial
From the Departments of Palliative Care and Rehabilitation Medicine, Breast Medical Oncology, and Anesthesiology and Pain Medicine, The University of Texas M.D. Anderson Cancer Center, and The Lyndon B. Johnson General Hospital, Houston, TX Address reprint requests to Eduardo Bruera, MD, Department of Palliative Care and Rehabilitation Medicine, Unit 0008, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: ebruera{at}mail.mdanderson.org
PURPOSE: To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). PATIENTS AND METHODS: Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point. RESULTS: Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed. CONCLUSION: Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention.
Fatigue is reported by 60% to 90% of patients with advanced cancer as their most frequent and debilitating symptom.1,2 Cancer fatigue is a multidimensional syndrome caused by a number of physical and psychosocial mechanisms,3,4 including tumor by-products, cytokines-causing cachexia, muscle loss, or deconditioning.5,6,10 In addition, opioids and other drugs are capable of contributing to fatigue by causing neurocognitive changes and hypogonadism.7-9 Chemotherapy and radiation therapy can cause fatigue both directly and indirectly through the production of anemia.5 Fatigue can interfere with a patient's ability to perform physical tasks and participate in social activities.3 The National Comprehensive Cancer Network has established guidelines for screening, evaluating, and treating cancer-related fatigue.2 These guidelines recommend the investigation of psychostimulants that have the potential to treat cancer-related fatigue. One such psychostimulant is methylphenidate, which stimulates the CNS; its mechanism of action is blockage of presynaptic dopamine reuptake.11,12 In patients with cancer, methylphenidate has been used to manage opioid-induced sedation,14,15 cognitive failure associated with brain tumors,16 and depression.13,17 Methylphenidate is usually administered twice a day, at breakfast and lunch, in order to minimize insomnia. However, because of its rapid onset of action and short half-life, methylphenidate may be effective in relieving fatigue when taken on an as-needed basis (patient-controlled) throughout the day. This flexible administration regimen may significantly improve the patient's quality of life. Our group has recently completed an open-label pilot study using patient-controlled methylphenidate, 5 mg every 2 hours, as needed, for the management of cancer-related fatigue.18 In 30 assessable patients, methylphenidate was temporarily associated with improvement in the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F) fatigue subscore from 17.5 (± 11) to 34.7 (± 10; P < .001), and the physical and functional subscores (P < .001), as well as the Edmonton Symptom Assessment System (ESAS) score for overall well-being and depression. There were no serious adverse effects, and no patients had to discontinue methylphenidate because of toxicity. Our preliminary results suggest that patient-controlled methylphenidate rapidly lessened fatigue and other symptoms; however, because of the open-label study design and the subjective end points, a placebo effect could not be ruled out. The purpose of this double-blind, randomized controlled trial was to evaluate the effectiveness of patient-controlled methylphenidate compared with that of a placebo on fatigue as measured by the FACIT-F.
The University of Texas M.D. Anderson Cancer Center institutional review board and the Committee for the Protection of Human Subjects at The University of Texas Health Science Center at Houston approved this protocol, and all participants provided written informed consent.
Patients
Methods We used restricted random assignment with random balance points from one to five blocks. A list of random assignments was prepared and the pharmacist entered the next eligible patient on the next available assignment line (eligible patients were identified by a research nurse). All members of the research team except for the investigational pharmacist were blinded to the treatment assignment throughout the study. The patients' cancer diagnosis, treatment history, concurrent medication(s), and Zubrod's performance status were recorded during the pretreatment assessment. The patients were asked to record in a daily diary the time at which they took a methylphenidate capsule, and to rate their fatigue on a numerical scale of 0 to 10 immediately before taking methylphenidate, and 2 hours afterward. Patients were also asked to record a diurnal fatigue diary in which intensity of fatigue was rated before breakfast, lunch, dinner, and before bedtime; using a 0 to 10 scale (0 = no fatigue; and 10 = worst possible fatigue). The patients were contacted daily by telephone by a research nurse, who ensured that the daily diaries and the diurnal fatigue diary were being completed, and asked questions about whether the patients had experienced adverse effects related to the treatment. Toxicity was assessed in accordance with National Cancer Institute Common Toxicity Criteria version 3.0. Toxicities were recorded if the patients reported a new onset of adverse effects or if they developed an increased grade of adverse effects from baseline. On day 8, the patients returned to the clinic for an evaluation. All patients were offered a 7-day supply of open-label methylphenidate 5 mg every 2 hours as needed for fatigue. On day 15, patients were off study after completion of the final assessment (described in the next three paragraphs). The patients were then given the option of continuing with methylphenidate for the management of their fatigue, or discontinuing the medication. The patients who elected to continue methylphenidate were provided with a 3-week supply. On day 36, the patients were contacted by a research nurse in person or by telephone for a follow-up evaluation. Although two measures used to assess fatigue were the (1) FACIT-F and (2) ESAS, the primary end point was the FACIT-F score. The FACIT-F is a well-validated quality-of-life instrument widely used for the assessment of cancer-related fatigue in clinical trials.19-22 It consists of 27 general quality-of-life questions divided into four domains (physical, social, emotional, and functional), plus a 13-item fatigue subscore. This 13-item fatigue subscore was the primary outcome of our study. The patient rates the intensity of fatigue and its related symptoms on a scale of 0 to 4. The total score ranged between 0 and 52, with higher scores denoting less fatigue. The ESAS was developed by our group to measure the response to nine common symptoms (pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep problems), and feeling of well-being in patients with cancer or chronic illness. A patient rates the intensity of symptoms on a numerical scale ranging from 0 to 10; 0 indicates "no symptom," and 10 indicates "worst possible symptom." These two assessment measures are both valid and reliable in assessing the intensity of symptoms.20 The FACIT-F and ESAS were administered at baseline and on days 8, 15, and 36. Sleep quality was assessed using sleep pattern assessment at baseline, days 8, 15, and 36. A 0 to 10 numerical scale was used to rate the difficulty in falling asleep, degree of restfulness in the morning, and overall problems with sleep, in which 0 indicates no problem, and 10 indicates the worst problem. The importance of lack of sleep was assessed using a numerical scale of 1 to 7. 1 indicates not important, and 7 indicates great importance. This scale has been used before in the assessment of insomnia.21 On days 8, 15, and 36, the patients were asked to rate the overall usefulness of the study drug on a scale of 1 (not beneficial) to 7 (greatly beneficial). In addition, the patients were asked to choose one of the following statements: "I felt better with the medication," "I felt no difference with the medication," or "I felt worse with the medication." Finally, the patients were asked to reply with "yes" or "no" to the statement, "I wish to continue the medication."
Statistical Analysis In a pilot study testing the effectiveness of methylphenidate for the management of cancer-related fatigue in 30 patients, the fatigue variable was measured using the FACIT-F at baseline and after 1 week. The pilot study showed using the FACIT-F that mean fatigue at baseline in 30 patients was 17.5 (± a standard deviation [SD] of 11.3), and use of methylphenidate improved the mean to 34.7 (± 10.0) at day 7. This is an improvement of more than 1.5 SDs. The mean difference in score (between baseline and after 1 week, matched by patient) was 17.1, with an SD of 13.95. Therefore, the change by patient between baseline and 7 days was approximately 1.2 SDs. We assumed that there might be a placebo effect and that the patients who received a placebo might also improve in their fatigue scores. We proposed to detect, on the basis of our sample size, a decrease in fatigue in the methylphenidate group over and above that in the placebo group, of half of the SDs, or approximately 7 on the FACIT-F scale. To declare this difference statistically significant, assuming a one-sided significance level of .05 and 80% power, we needed to enter 50 assessable patients per group into this study, and we therefore entered 125 patients to allow for a possible 20% dropout rate. A one-sided significance test was used only when planning the study based on the highly significant results observed in our pilot study. All results reported in this study are based on two-sided tests. A t test was used to evaluate differences in fatigue between groups unless the data appeared to be non-normally distributed, in which case a Wilcoxon rank sum test was used to evaluate differences between groups. Other variables to be analyzed using similar methods include other subscales on the FACIT-F, ESAS variables, sleep characteristics, and overall benefit. We also summarize by group the number of adverse events and the mean intensity of fatigue before breakfast, lunch, dinner, and before bedtime.
A total of 143 patients underwent screening for possible inclusion in the study and were asked to participate in this trial. Of these, 112 patients consented and underwent random assignment (Fig 1). Fifty-two patients in the methylphenidate group and 53 in the placebo group were assessable for analysis. A total of seven patients were withdrawn from the study: two were hospitalized because of disease progression, one was nonadherent, one was unavailable for contact, and two never received the study drug.
The patients' characteristics are summarized in Table 1. There were no significant differences between the two study arms based on any demographic characteristic, nor on baseline clinical or medical variables. There was no significant difference in the intensity of symptoms at baseline in any group as measured by FACIT-F and ESAS.
Table 2 shows the mean difference in symptom intensity between methylphenidate and placebo at day 8. There was no significant difference in improvement of fatigue intervention between methylphenidate and placebo according to our primary end point subscore (FACIT-F; P = .31); or according to ESAS 0 to 10 fatigue score (P = .14). Because of the nature of this study, the remaining analysis should be considered exploratory.
At day 15, 73 (73%) of 100 patients reported continued improvement in fatigue (a decrease of two points from baseline by ESAS). The mean (± SD) fatigue scores at day 15 using FACIT-F and ESAS were 31.9 (± 10.7), as compared with 16.9 (± 7.9) at baseline (P < .01), and 4.0 (± 2.3) as compared with baseline 7.5 (± 1.8; P < .01), respectively. Table 3 highlights the sustained significant improvement of symptom intensity between day 15 and day 36 in patients taking methylphenidate.
The mean (± SD) daily number of capsules of methylphenidate and placebo taken by the patients between days 1 and 8 were 2.3 (± 1.0) and 2.1 (± 1.0), respectively (P = NS). Overall mean intensities of fatigue immediately before and 2 hours after taking methylphenidate were 5.5 and 4.5 (difference score, –0.9 [± 1.3]), respectively, and intensities before and after taking the placebo were 5.2 and 4.5 (difference score, –0.7 [± 1.2]), respectively. The differences between methylphenidate and placebo were not statistically significant. Sleep assessments at baseline and day 8 are shown in Table 4. Both methylphenidate and placebo group had clinical insomnia at baseline and had significant improvement after methylphenidate and placebo. However, there was no significant difference in the improvement of insomnia between methylphenidate and placebo group.
Table 5 summarizes the toxicities between the methylphenidate and placebo groups during the double-blind phase. The grade and frequency of toxicity were similar in the two groups. Only one patient, in the placebo group, withdrew from the study because of grade 3 restlessness during the double-blind phase.
Figure 2 shows that the intensity of fatigue tends to increase at the beginning of the day and gradually decrease by the end of the day. One week after treatment, the patients were asked how they felt about the medication. In the methylphenidate group, 28 patients (54%) reported feeling better, 22 (42%) reported feeling no difference, and two (4%) reported feeling worse. In the placebo group, 23 (43%) reported feeling better, 30 (57%) reported feeling no difference, and no one reported feeling worse. Overall, of the patients in the methylphenidate group, 28 (54%) reported no benefit or minimal benefit, and 24 (46%) reported moderate benefit or of great benefit. In contrast, in the placebo group, 39 (74%) of the patients reported no benefit or minimal benefit, and 14 (26%) said that the medication was of moderate benefit or of great benefit. All patients received a daily telephone call by a blinded research nurse for the purpose of symptom assessment and daily follow-up. Telephone calls were also conducted on weekends and holidays; and since the research nurses were blinded to the type of treatment, we assumed that this intervention was identical in both groups.
Only one patient did not wish to continue the medication, on day 8. Among the 100 patients who completed the study through day 15, 91 wished to continue the medication, and 70 patients completed 5 weeks of treatment. Pearson correlation between ESAS fatigue and FACIT-F fatigue subscores at baseline, day 8, and day 15 ranged from 0.63 to 0.77.
The overall improvements in the fatigue subscale in the FACIT-F (7.5 for placebo and 9.6 for methylphenidate), was lower than that observed in our initial pilot study (17 points). This improvement was likely the result of the double-blind controlled nature of this study. However, in both groups, approximately 90% of patients receiving the study medication or placebo chose to continue the medication after the study was completed. Our findings reinforce the importance of conducting placebo-controlled trials to assess symptomatic outcomes. We observed a similar improvement of fatigue and other symptom scores both in the patients receiving methylphenidate and in those receiving placebo. Both groups experienced a dramatic lessening in the intensity of fatigue as measured by the FACIT-F and the ESAS (Tables 2). These results were sustained during the open-label methylphenidate phase at days 15 and 36, respectively (Table 3). Although longer studies might be desirable, previous research with methylphenidate has shown that this drug has a very rapid onset of action and that significant differences can be observed for symptoms such as pain, sedation, and fatigue in open studies within 3 to 7 days.14,18 In previous studies, we did not observe such a striking improvement in fatigue and other symptoms in patients receiving placebo.14,15,23-28 One of the main differences between this study and previous placebo-controlled trials conducted by our group was the daily telephone call by a research nurse. We believe that this telephone call was a powerful intervention, enhancing the patient's overall symptom relief and comfort. Future studies should assess the effects of methylphenidate in patients not receiving daily telephone calls from a nurse. In addition, clinical trials should be conducted to determine the effects of a regular phone call from a nurse on the improvement of different target symptoms such as fatigue. Our study found sustained improvement in patients with fatigue at weeks 2 and 5 (who did not receive daily phone calls from a research nurse after day 8). In the absence of a placebo-controlled group, we are not able to determine if these findings reflect an independent effect or are simply an extension of placebo effect. Patient-controlled methylphenidate was very well tolerated, as shown by the absence of serious adverse events at day 8 compared with those found in the placebo group and also during the follow-up at weeks 2 and 5. Contrary to our experience with methylphenidate for opioid-induced sedation, our patients did not appear to increase the number of daily doses over time.14,15 This finding is similar to that in our pilot study18 and suggests that tolerance to methylphenidate is unlikely to become a major problem when the drug is used for managing fatigue. Our findings (Table 4) suggest that methylphenidate and placebo resulted in a similar improvement in sleep quality. Our results regarding the timing of fatigue suggest that during clinical trials, fatigue should be assessed at the same time of day in order to control for circadian variations in the intensity of this symptom. Our results suggest that methylphenidate is not superior to a placebo for the management of fatigue in patients with advanced cancer. Future research should assess the role of a higher dose of methylphenidate; a longer observation period, reducing the potential carryover of the placebo effect; and a telephone call from a nurse in lessening fatigue and other symptoms in patients with cancer. Given the currently available data, there is no rationale for the regular use of methylphenidate in the management of cancer-related fatigue.
The authors indicated no potential conflicts of interest.
Presented in part at the 41st Annual Meeting of American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
24/30); a hemoglobin level of at least 10 g/dL within 2 weeks of enrollment in the study; no history of tachycardia or uncontrolled hypertension; no presence of glaucoma, severe anxiety disorders, or substance abuse; and no administration of monoamine oxidase inhibitors, tricyclic antidepressants, or clonidine. 
