乌鸦传媒

The psychostimulant methylphenidate proved no better than placebo for relieving cancer-related fatigue (CRF) in a randomized trial.

After 6 weeks of treatment in palliative care patients with advanced cancer, those allocated to methylphenidate had a 2-point greater improvement fatigue score as compared with placebo, a nonsignificant difference. After 10 weeks, the methylphenidate group still had only a nonsignificant improvement versus placebo.

Scores on quality-of-life (QoL) and symptom outcomes also did not differ between groups at 6 weeks, with the exception of a modest improvement in depression in the methylphenidate arm, reported Patrick Charles Stone, MD, of University College London, and coauthors in the .

"On the basis of our findings, we do not recommend the use (or further trials) of methylphenidate for fatigue in patients with advanced cancer receiving palliative care," the authors concluded. "However, given the absence of major AEs [adverse events], it would be safe to continue to explore its use in future clinical trials for other symptoms (e.g., low mood or opioid-related drowsiness), in combination with other interventions (e.g., exercise or psychological therapies) or in different populations (e.g., post-treatment fatigue)."

The authors of an agreed that the negative results should not close the door to future studies of methylphenidate or other psychostimulants.

"We believe there remains room for further trials in this area, particularly in subpopulations that have demonstrated promise, using measures that are sensitive to the specific aspect of fatigue that is most likely to demonstrate a benefit," wrote Camilla Zimmerman, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and coauthors. "Considering the multifactorial nature of CRF, combination therapies of methylphenidate with other CRF treatments such as physical activity or cognitive behavioral therapy should also be considered."

The study's negative outcome continued a pattern of inconsistency with clinical trials of psychostimulants such as methylphenidate in patients with cancer or AIDS, owing in large part to challenges in trial design, William Breitbart, MD, of Memorial Sloan Kettering Cancer Center in New York City, told 乌鸦传媒 via email.

"Thus, we've seen several trials that show benefit and multiple trials that show no benefit," said Breitbart, a member of the National Comprehensive Cancer Network (NCCN) Guidelines Panel for Cancer-Related Fatigue.

Challenges of such trials include:

• Choosing a sufficiently severe fatigue threshold to allow adequate room for improvement in fatigue; the current study used >3 on a scale of 10
• Screening out patients with clinical depression to ensure the study assesses the effects of methylphenidate on cancer-related fatigue and not fatigue associated with depression
• A study should focus on a homogeneous population (e.g., patients with prostate cancer treated with hormonal therapy); patients with advanced cancer have multiple potential causes of fatigue which might respond differently to methylphenidate
• The placebo effect for a subjective symptom such as fatigue can be quite prolonged, and active drug and placebo may not separate for 4-6 weeks or more, so longer trials are necessary
• Assessing fatigue with scales that focus only on subjective report -- without studying cognitive effects and physical endurance effects, as well -- reduces a multi-dimensional symptom to only one dimension, which may be insufficient to draw conclusions

"The NCCN Guidelines support the use of psychostimulants is not simply based on the published trials, but also on clinical judgment and expertise," said Breitbart. "Clinicians utilize methylphenidate in clinical practice and often see benefits in fatigue. Treatment effects are often improved further if the underlying causes of fatigue can be simultaneously treated (e.g., anemia). However, a consensus of clinicians treating clinical fatigue in patients who are fatigued from cancer treatments of other etiologies find methylphenidate to be useful."

Stone and colleagues noted that the NCCN "advises that methylphenidate can be considered in selected patients, but should be used cautiously and not until treatment and disease-specific morbidities have been characterized and excluded." The guideline points out that optimal dosing and schedule have yet to be determined. Meanwhile, the European Society for Medical Oncology guideline on cancer-related fatigue "is noncommittal about the issue," they wrote.

Given the ongoing uncertainty about methylphenidate's effectiveness, the authors performed a placebo-controlled trial of individually titrated doses of the drug in patients with advanced cancer. The primary objective was fatigue scores after 6 weeks of treatment. Secondary outcomes included QoL, AEs, activities of daily living, appetite, patient satisfaction, survival, and need for other medications. Fatigue was assessed by means of the , and significant baseline fatigue was defined as >3.

Data analysis included 159 patients (76 men, 83 women) who had a mean age of 63.7. The most common cancers in both groups were breast, lung, prostate, and lower gastrointestinal. Other baseline characteristics were balanced between the methylphenidate and placebo arms.

AEs had no discernible patterns to suggest greater harm from methylphenidate than placebo. A total of 25 serious AEs occurred in each arm.

After 6 weeks, the FACIT-F score in the methylphenidate group exceeded that of the placebo group by 1.97 (95% CI -0.95 to 4.90, P=0.186). A sensitivity analysis resulted in a difference of 2.05 in favor of methylphenidate, also nonsignificant. A threshold analysis produced a difference of 3.15 in favor of methylphenidate, still less than a minimally clinically important difference (MCID) of 5.

An analysis at 10 weeks showed a difference of 2.20 in favor of methylphenidate, still less than the MCID.

Mortality was similar in the two groups.

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