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Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3475-3481 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.9231 Donepezil for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial
From the Department of Palliative Care and Rehabilitation Medicine, Department of Breast Medical Oncology, and Department of Cancer Pain Management, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Eduardo Bruera, MD, Department of Palliative Care and Rehabilitation Medicine, Unit 008, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ebruera{at}mdanderson.org
Purpose: To evaluate the effectiveness of donepezil 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 fatigue score Results: Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed. Conclusion: Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.
Fatigue is the most frequent symptom in advanced cancer patients.1-4 It is a multidimensional syndrome3-9 that can impair the quality of life of cancer patients. There are no available data in the literature regarding the frequency of fatigue for different primary tumors. The current management of fatigue includes the treatment of reversible causes such as mood disorders, metabolic abnormalities, or anemia. Unfortunately, fatigue persists in most patients even after the correction of these abnormalities. A number of pharmacologic clinical trials including paroxetine10,11 and methylphenidate12 have failed to improve cancer-related fatigue (CRF). At present, there is no proven pharmacologic treatment for the symptomatic management of CRF. The etiology of CRF remains unknown.10,11 One of the several explanatory theories that have been proposed for CRF is autonomic failure.5,11 This syndrome results from decreased cholinergic and adrenergic output to the periphery and is common in patients with advanced cancer.5,6 These patients have evidence of decreased cholinergic activity as demonstrated by gastroparesis, early satiety, and chronic nausea.7,8 It is possible that donepezil could improve subjective fatigue in these patients by increasing central cholinergic activity. Donepezil is a long-acting selective acetylcholinesterase inhibitor with linear pharmacokinetics, no significant drug interactions, and good tolerance. It is very well absorbed, mostly bound to protein, and has an excellent oral bioavailability. Its main indication for use is Alzheimer's disease. Common adverse effects of donepezil are insomnia, nausea, and diarrhea. Our group conducted a 1-week open-label pilot study using donepezil 5 mg/d for the management of opioid-induced sedation and related symptoms in patients receiving opioids for cancer pain.9 In 20 assessable patients, donepezil was associated with improvement in the Functional Assessment for Chronic Illness Therapy–Fatigue (FACIT-F) score and the Edmonton Symptom Assessment System (ESAS) drowsiness and fatigue scores by day 7. The treatment was well tolerated; five patients discontinued donepezil mainly because of nausea. However, because of the open-label study design and the subjective end points, a placebo effect could not be ruled out. A pilot study by Shaw et al13 suggested that fatigue improved significantly after treatment with donepezil in irradiated brain tumor patients (P = .03). The results of our initial study justified additional research on the effects of donepezil on CRF. Therefore, we conducted a prospective, double-blind, randomized, controlled trial to evaluate the effectiveness of donepezil compared with that of a placebo on fatigue as measured by the FACIT-F fatigue subscale in patients with advanced cancer.
Patients Patients with advanced cancer (defined as locally recurrent or metastatic) seen at the Palliative Care or Pain Clinics at the M.D. Anderson Cancer Center (Houston, TX), or by the oncologists at Lyndon B. Johnson General Hospital (Houston, TX) were approached to participate in this study. Both institutional review boards approved this protocol and all participants provided written informed consent. Inclusion criteria were age  18 years; fatigue score 4 on a scale of 0 to 10 (10 being worst possible fatigue) for more than 1 week; normal Mini-Mental State Examination according to age and educational level; willingness to engage in follow-up visits with a research nurse by telephone on days 1 to 7 and 11, and at the center on days 8 and 15. Exclusion criteria were women who were pregnant or lactating; use of tube feeding; history of uncontrolled atrial fibrillation, uncontrolled hypertension, ongoing angina pectoris, ongoing heart failure, recent myocardial infarction, or urinary incontinence; presence of concurrent nausea, vomiting, or diarrhea; major contraindication to donepezil; major changes expected during the next 7 days (eg, hospitalization); administration of anticholinergic agents; and hemoglobin level less than 10 g/dL within the last 4 weeks before enrollment onto the study.
Methods We used restricted randomization 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. The treatment assignment of individual patients was blinded to all members of the research team throughout the study except for the investigational pharmacist. The patients' cancer diagnosis, concurrent medications, Zubrod performance status, ESAS, bowel movements during a period of 1 week, FACIT-F, cognition (Symbol Digit Modality Test), sleeping quality assessment, toxicity assessment, and Mini-Mental State Examination were recorded during the pretreatment assessment. A research nurse contacted the patients by daily telephone calls (days 1 to 7) for symptoms and treatment toxicity assessment. Symptoms were assessed using the ESAS and toxicity was assessed in accordance with the 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, patients were evaluated at the clinic. At the end of the first week, patients were asked to choose blindly whether they wished to continue the medication. Those who chose to continue were administered open-label donepezil for 1 week. On day 15, patients returned for a final assessment and those who chose to continue donepezil were provided with a 2-week supply. Each patient's primary doctor was provided a letter describing the nature of the study and the characteristics of donepezil. The primary end point was the 13-item fatigue score of FACIT-F. The FACIT-F is a well-validated quality-of-life instrument widely used for the assessment of CRF.15-18 It consists of 27 general quality-of-life questions divided into four domains (physical, social, emotional, and functional), plus a 13-item fatigue subscale. The patient rates the intensity of fatigue and its related symptoms on a scale of 0 to 4. The total score range between 0 and 52, with higher scores denoting less fatigue. The ESAS was developed by our group to measure 10 common symptoms (pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and feeling of well-being) in patients with cancer or chronic illness. The patient rates symptom intensity from 0 to 10 (0 = no symptom). The FACIT-F and ESAS fatigue scores are valid and reliable tools for the assessment of fatigue.16,17 The FACIT-F was administered at baseline and on days 8 and 15. The ESAS was administered at baseline, and days 1 to 8, 11, and 15. Sleep quality was assessed using Sleep Pattern Assessment at baseline and days 8 and 15. A numerical scale from 0 to 10 (10 = worst) was used to rate the difficulty in falling asleep, restfulness in the morning, and problems with sleep. The importance of lack of sleep was assessed using a numerical scale of 1 to 7 (7 = great importance). This scale has been used before in the assessment of insomnia.18 Bowel movements were assessed during a period of 1 week at baseline and days 8 and 15 by measuring the daily number, volume, and consistency of stools, and the change in constipation (worse, no change, and better). Bowel movements were assessed to test if donepezil was capable of improving constipation. On days 8 and 15, the patients were asked to rate the overall benefit of the study drug on a scale of 1 to 7 (7 = greatly beneficial). In addition, patients were asked to choose if they felt better, no difference, or worse. Finally, they were asked to reply with "yes" or "no" to the statement "I wish to continue the medication."
Statistical Analysis We assumed that, on average, patients who received placebo might not change in their fatigue scores. Using information from the previous study, we proposed to detect a decrease in fatigue in the donepezil group over and above that in the placebo group of one half of a standard deviation, which would be approximately 7 on the FACIT-F fatigue score. 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 onto this study. Assuming a potential dropout rate of up to 20%, we needed to enroll a total of approximately 126 patients onto this study. A t test was used to evaluate the difference between groups unless the data were not normally distributed, in which case a Wilcoxon rank sum test was used to evaluate the difference between groups. Fifty assessable patients allowed us to detect a difference between groups for other variables of approximately one half of a standard deviation assuming a one-sided significance level of .05 and 80% power. Other variables analyzed using similar methods included other subscales on the FACIT-F, ESAS variables, sleep characteristics, constipation, cognition, and overall benefit. Statistical analysis was performed with SAS version 9.1 software (SAS Institute Inc, Cary, NC)
A total of 142 patients with advanced cancer consented and underwent random assignment between September 2004 and July 2006 (Fig 1). A total of 39 patients (27%) were not assessable. The first 14 patients (seven from each group) were not assessable because the FACIT-F questionnaire was missing the fatigue subscale page. This protocol violation was noted and corrected. Details on assessable patients are summarized in Figure 1; 103 patients (73%; 47 in the donepezil group and 56 in the placebo group) were assessable for the final analysis.
Patient characteristics are summarized in Table 1. There were no significant differences between the two study arms on baseline clinical variables or baseline fatigue intensity as measured by FACIT-F (P = .64).
Table 2 lists the mean difference in symptom intensity between baseline and day 8. There was no significant difference between donepezil and placebo according to FACIT-F (P = .57) and ESAS fatigue scores (P = .18). Because of the nature of this study, the remaining analysis should be considered exploratory. Figure 2 shows the rapid improvement in ESAS 0 to 10 fatigue score during the blind phase.
Table 3 lists the effects of donepezil and placebo on sleep quality. Patients in the donepezil group had no statistical difference in any of the four-item scores of sleep pattern assessment when compared with placebo. There was a trend toward improvement of sleep quality at day 8 in both groups. The difference between both drugs was not significant.
Table 4 summarizes the toxicities between the donepezil and placebo groups during the double-blind phase. The grade and frequency of toxicities were similar in both groups.
At day 8, 16 (30%) and 28 patients (43%) reported feeling better, 34 (63%) and 37 patients (57%) reported feeling no difference, and four (7%) and zero patients (0%) reported feeling worse in the donepezil and placebo groups, respectively (P = .03). Overall, 45 (85%) of 53 patients and 51 (78%) of 65 patients reported no benefit or minimal benefit, and eight of 53 (15%) and 14 (22%) of 65 patients reported moderate or great benefit in the donepezil and placebo groups, respectively (P = .44). There was no significant difference in constipation, stool amount, consistency, and change in constipation on day 8 between groups. There was no significant difference in cognition improvement between day 15 and baseline between groups. On day 8, 50 (94%) of 53 patients from the donepezil group and 63 (97%) of 65 patients from the placebo group chose to continue the drug (P = .65) and were offered open-label donepezil. Ninety-six patients continued taking the open-label donepezil until day 15. Thirty-two (73%) of 44 patients from the donepezil group and 39 (75%) of 52 patients from the placebo group chose to continue the treatment on day 15 (P = .80). The Spearman correlation coefficient between ESAS fatigue and FACIT-F fatigue scores at baseline, day 8, and day 15 ranged from –0.74 to –0.45, showing that the two measures were highly associated with each other at each time point (all P < .0001).
Our results confirm those of our previous pilot study, but also found improvement for patients in the placebo group. The overall improvement in the fatigue subscale (7.2 for placebo and 6 for donepezil) was somewhat lower than that observed in our initial study (9.4 points). These results were likely the result of the double-blind, controlled nature of this study. Our findings reinforce the importance of conducting placebo-controlled trials to assess symptomatic outcomes. We observed similar improvement of fatigue in both groups as measured by FACIT-F and ESAS (Table 2). These results were sustained during the open-label donepezil phase at days 11 and 15, respectively. Our study found significant improvement in drowsiness after both donepezil and placebo (Table 2). This result is in contrast to results from a previous open report9 regarding the effect of donepezil on sedation. Randomized controlled studies with sedation as a primary outcome should be conducted before donepezil can be recommended for sedation. Our previous study and other authors' reports suggested that a clinical effect could be observed rapidly in patients receiving donepezil: Bruera et al9 reported improvement of sedation and fatigue as early as day 3, and Slatkin et al14 reported improvement of sedation as early as "few days" (sic) from the initiation of donepezil. However, donepezil needs 15 days to reach steady-state levels. The inconvenience of long-latency drugs could make donepezil less attractive to researchers because of the short life span of this particular group of patients. Studies on the role of such drugs could be conducted at earlier stages of cancer. Our previous pilot study with donepezil for opioid-induced sedation observed significant and rapid improvement in fatigue. In that study, the main criterion for eligibility was opioid-induced sedation. In the current study, the main criterion for eligibility was fatigue, and our results suggested that donepezil was not effective for the treatment of this symptom. Our previous pilot studies with donepezil9 and methylphenidate19 found excellent preliminary results in the improvement of fatigue and sedation. Those results were not confirmed in placebo-controlled trials.12 When tested in a placebo-controlled trial, the drug and placebo resulted in dramatic improvement of fatigue and other symptoms. In both cases, a daily telephone assessment by a nurse took place. It is possible that the telephone intervention may have resulted in symptom improvement. Future studies should address the role of regular telephone call by a nurse for symptom distress improvement; it is possible that a beneficial effect of the drug may have been masked by the very major response to placebo when accompanied by the telephone call. Future studies ideally should not include telephone calls or should be conducted in a four-arm study: drug-placebo with and without telephone call assessments. We currently are conducting a study of methylphenidate using such a design. Our previous preliminary data suggested that donepezil could reduce daytime sedation.9 Patients in both groups were experiencing high scores on the sleep pattern assessment at baseline, with a trend toward improvement on day 8. Unfortunately, our trial found no significant effect for donepezil on quality of sleep on day 8. It is likely that the increased care received with daily telephone calls resulted in the trend toward better sleep in both groups. Donepezil was well tolerated; adverse effects were similar to those described in other settings and included mostly nausea. In all patients, these adverse effects disappeared rapidly on discontinuation of donepezil. Only 16 (30%) of 54 and 28 (43%) of 65 patients perceived usefulness at the end of the double-blind phase in donepezil and placebo groups, respectively. The choice of the overwhelming majority to continue the open-label treatment was probably due to the minimal toxicity of this treatment and to the expectation of improvement if patients believed they had received placebo during the blind phase of the study. Fatigue has been reported as an adverse effect by some patients with Alzheimer's dementia treated with donepezil. We believe that it is unlikely that donepezil has contributed to patients' fatigue, especially with the absence of any significant difference in fatigue scores between the two groups at any time during the study. If donepezil enhanced fatigue, patients in this group would be expected to report more fatigue at day 15 than at baseline. At the recommended starting dose (5 mg/d), donepezil was not superior to placebo in CRF management. The dose can be increased to 10 mg/d after 4 to 6 weeks. Because of the distressing nature of CRF and the short expected survival of these patients, it would be inappropriate to wait such a long time before improvement can be observed. Our findings suggest that autonomic failure may be less associated with CRF compared with other conditions such as dysautonomia or chronic fatigue syndrome. In a recent study,5 we found a high frequency of autonomic failure in advanced cancer patients, but the syndrome was not associated significantly with fatigue. It is likely that CRF is more related to the presence of proinflammatory cytokines,20 cachexia,21 deconditioning,21 and mood abnormalities21 rather than reversible cholinergic failure. Clinical practice guidelines have been developed by the National Comprehensive Cancer Network for CRF treatment. These guidelines highlight our limited understanding about the pathophysiology and lack of effective treatment for this symptom. Future research should focus on pharmacologic interventions that modulate cytokines, such as thalidomide22 and corticosteroids23-28; interventions that treat hypogonadism, such as testosterone,5 and autonomic failure such as midodrine29; and psychostimulants such as methylphenidate10,12 and modafinil.30 Future research also is needed to focus on nonpharmacologic interventions such as exercise31 in patients with CRF. We conclude that after 1 week of treatment, our negative trial found that donepezil was not superior to placebo in the treatment of CRF. Given these results, we do not recommend the regular use of donepezil in CRF management.
The author(s) indicated no potential conflicts of interest.
Conception and design: Eduardo Bruera Administrative support: Valerie A. Poulter Provision of study materials or patients: Vicente Valero, Larry C. Driver Collection and assembly of data: Badi El Osta, Be-Lian Pei, Loren Shen Data analysis and interpretation: Eduardo Bruera, Badi El Osta, J. Lynn Palmer Manuscript writing: Eduardo Bruera, Badi El Osta, J. Lynn Palmer Final approval of manuscript: Eduardo Bruera, J. Lynn Palmer Other: Badi El Osta [Coordination between different authors]
Supported in part by National Institutes of Health Grants No. R01NRO10162-01A1 and RO1CA122292-01 (E.B.). Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Vogelzang N, Breitbart W, Cella D, et al: Patient, caregiver, and oncologist perceptions of cancer-related fatigue: Results of a tri-part assessment survey. Semin Hematol 34:4-12, 1997 (suppl 2)[Medline] 2. National Comprehensive Cancer Network:NCCN Clinical Practice Guidelines in Oncology: Cancer-related fatigue, version 2, 2007. http://www.nccn.org/professionals/physician_gls/PDF/fatigue.pdf 3. Bruera E, Neumann C, Brenneis C, et al: Frequency of symptom distress and poor prognostic indicators in palliative cancer patients admitted to a tertiary palliative care unit, hospices, and acute care hospitals. J Palliat Care 16:16-21, 2000[Medline] 4. El Osta B, Bruera E: Models for palliative care delivery, in: Bruera E, Higginson I, Ripamonti C, et al (eds): Textbook of Palliative Medicine. London, United Kingdom, Hodder Arnold Publication, 2006, pp 266-276 5. Strasser F, Palmer JL, Schover LR, et al: The impact of hypogonadism and autonomic dysfunction on fatigue, emotional function, and sexual desire in male patients with advanced cancer: A pilot study. Cancer 107:2949-2957, 2006[CrossRef][Medline] 6. Walsh D, Nelson KA: Autonomic nervous system dysfunction in advanced cancer. Support Care Cancer 10:523-528, 2002[CrossRef][Medline] 7. Sweeney C, Neuenschwander H, Bruera E: Fatigue & asthenia, in Doyle D, Hanks G, Cherny NI, Calman K (eds): New York, NY, Oxford Textbook of Palliative Medicine, 2004, pp 560-568 8. Miaskowski C. Portenoy R.: Assessment and management of cancer related fatigue, in Berger A, Portenoy R, Weissman D (eds): Principles and Practice of Palliative Care and Supportive Oncology (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 141-153 9. Bruera E, Strasser F, Shen L, et al: The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: A pilot study. J Pain Symptom Manage 26:1049-1054, 2003[CrossRef][Medline] 10. Morrow GR, Hickok JT, Roscoe JA, et al: Differential effects of paroxetine on fatigue and depression: A randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 21:4635-4641, 2003 11. Roscoe JA, Morrow GR, Hickok JT, et al: Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat 89:243-249, 2005[CrossRef][Medline] 12. Bruera E, Valero V, Driver L, et al: Patient-controlled methylphenidate for cancer fatigue: A double-blind, randomized, placebo-controlled trial. J Clin Oncol 24:2073-2078, 2006 13. Shaw EG, Rosdhal R, D'Agostino RB Jr, et al: Phase II study of donepezil in irradiated brain tumor patients: Effect on cognitive function, mood, and quality of life. J Clin Oncol 24:1415-1420, 2006 14. Slatkin NE, Rhiner M, Bolton TM: Donepezil in the treatment of opioid-induced sedation: Report of six cases. J Pain Symptom Manage 21:425-438, 2001[CrossRef][Medline] 15. Cella DF, Tulsky DS, Gray G: The functional assessment of cancer therapy scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993 16. Yellen SB, Cella DF, Webster K, et al: Measuring fatigue and other anemia-related symptoms with the functional assessment of cancer therapy (FACT) measurement system. J Pain Symptom Manage 13:63-74, 1997[CrossRef][Medline] 17. Wu HS, McSweeny M: Measurement of fatigue in people with cancer. Oncol Nurs Forum 28:1371-1386, 2001[Medline] 18. Reddy SG, Pace E, Zhang T, et al: What is a clinically significant improvement in the intensity of fatigue among cancer patients? J Clin Oncol 24:483s, 2006 (suppl; abstr 8560) 19. Bruera E, Driver L, Barnes EA, et al: Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: A preliminary report. J Clin Oncol 21:4439-4443, 2003 20. Lee BN, Dantzer R, Langley K, et al: A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation 11:279-292, 2004[CrossRef][Medline] 21. Del Fabbro E, Dalal S, Bruera E: Symptom control in palliative care: Part II. Cachexia/anorexia and fatigue. J Palliat Med 9:391-408, 2006[CrossRef][Medline] 22. Bruera E, Neumann CM, Pituskin E, et al: Thalidomide in patients with cachexia due to terminal cancer: Preliminary report. Ann Oncol 10:857-859, 1999 23. Lundstrom SH, Furst CJ: The use of corticosteroids in Swedish palliative care. Acta Oncol 45:430-437, 2006[CrossRef][Medline] 24. Yennurajalingam S, Bruera E: Palliative management of fatigue at the close of life: "It feels like my body is just worn out. " JAMA 297:295-304, 2007 25. Bruera E, Roca E, Cedaro L, Carraro S, Chacon R: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69:751-754, 1985[Medline] 26. Porock D, Kristjanson LJ, Tinnelly K, et al: An exercise intervention for advanced cancer patients experiencing fatigue: A pilot study. J Palliat Care 16:30-36, 2000[Medline] 27. Inoue A, Yamada Y, Matsumura Y, et al: Randomized study of dexamethasone treatment for delayed emesis, anorexia and fatigue induced by irinotecan. Support Care Cancer 11:528-532, 2003[CrossRef][Medline] 28. Hardy JR, Rees E, Ling J, et al: A prospective survey of the use of dexamethasone on a palliative care unit. Palliat Med 15:3-8, 2001 29. Morrow GR, Ryan JL, Kohli S, et al: Modafinil (Provigil) for persistent post-treatment fatigue: An open label study of 82 women with breast cancer. MASCC International Symposia, Toronto, Canada, June 22-24, 2006 (abstr 11-070) 30. Naschitz J, Dreyfuss D, Yeshurun D, Rosner I: Midodrine treatment for chronic fatigue syndrome. Postgrad Med J 80:230-232, 2004 31. Dimeo F, Stieglitz R, Novelli-Fischer U, et al: Effects of physical activity on the fatigue and psychological status of cancer patients during chemotherapy. Cancer 85:2273-2277, 1999[CrossRef][Medline] Submitted January 24, 2007; accepted May 11, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
