Moraska, A. R., Sood, A., Dakhil, S. R., Sloan, J. A., Barton, D., Atherton, P. J., . . . Loprinzi, C. L. (2010). Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. Journal of Clinical Oncology, 28, 3673–3679.

To evaluate the efficacy of long-acting methylphenidate in alleviating cancer-related fatigue (CRF), assess tolerability, and determine the effects on quality of life (QOL) in patients with CRF. Prior studies of methylphenidate have yielded mixed results. The drug used here was a mixture of d and l isomers of methylphenidate.

Patients were stratified according to disease stage, baseline fatigue scores, and whether they were receiving concomitant cancer treatment. They were then randomized to receive methylphenidate or placebo for four weeks. Patients took one tablet (18 mg of long-acting methylphenidate) on days 1 to 7, two tablets (36 mg) on days 8 to 14, and three tablets (54 mg) on days 15 to 28. Tablets were to be taken in the morning. A standard dose modification procedure was used in case of adverse effects attributed to the study drug.

• The final evaluable sample included 125 patients (57%–60% female). 
• Patients had a history of CRF defined by a score of 4 or more on a 10-point fatigue screening scale.
• Mean age was 59.2 years (standard deviation [SD] = 11.23 years) in the methylphenidate arm and 60.6 years (SD = 13.82 years) in the placebo arm. 
• Of the patients, 29% to 38% had breast cancer across the study groups. Other diagnoses included lung, colon, prostate, and mixed cancers.
• Patients had an Eastern Cooperative Group (ECOG) performance status of 0 to 2. 
• Patients had a life expectancy of at least six months. 
• Patients were excluded if they had any other cause of fatigue, brain tumor or metastases, and psychiatric disorders, among other exclusions.

• Multisite
• Collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic

The study was a double-blind, randomized, placebo-controlled trial.

• Brief Fatigue Inventory (BFI), completed weekly
• Short Form 36 Health Survey (SF-36) Vitality subscale
• Weekly linear analog self-assessment items used in North Central Cancer Treatment Group (NCCTG) clinical trials for QOL measures
• Pittsburgh Sleep Quality Index (PSQI), completed at study entry and week 4
• Subject Global Impression of Change (SGIC) was completed at the end of week 4 to measure patients’ perceived improvements in QOL, physical condition, and emotional state.
• Adverse events and drug toleration were assessed with symptom experience diaries completed at baseline and weekly by patients.
• Common Terminology Criteria (CTC) v3.0 was used by providers to grade adverse events at baseline and at each weekly evaluation via weekly telephone calls.

In advanced stage disease (stage III–IV), mean improvement in fatigue was 19.7 with methylphenidate and 2.1 with placebo (p = 0.02) Early stage patients had less improvement with methylphenidate than those receiving placebo. Similar trends were seen in SF-36 measures; however, differences between groups were not statistically significant. Self-reported adverse events showed a significant increase in nervousness (p = 0.003) and appetite loss (p = 0.034) in the methylphenidate arm. Individuals in the placebo arm reported improvements in self-reported adverse effects in nervousness, shakiness, appetite loss, abdominal pain, and sex drive. Both study groups were similar in terms of gender distribution, age, disease stage, and other baseline measures.

The study demonstrated benefit for d-methylphenidate compared with placebo in alleviating CRF. Methylphenidate appeared to have some benefit in patients with advanced stage of disease.

There appeared to be some benefit of long-acting methylphenidate in patients with more advanced disease; however, these patients also experienced adverse effects. For use in these patients, benefits in terms of fatigue would need to be weighed against the adverse effects for individual patients from the patient's perspective.

The study findings suggest that further research on effectiveness, particularly in patients with more advanced disease, is warranted.