A phase II randomized, placebo-controlled, double blind trial of a eugeroic agent in 642 cancer patients reporting fatigue during chemotherapy: A URCC CCOP study

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 2 de junio del 2008

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Presenter: G. R. Morrow
Presenter's Affiliation: U. of Rochester Medical Center, Rochester, NY
Type of Session: Scientific

Background

  • Cancer-related fatigue (CRF) is one of the most common side effects of cancer and its treatment, and has been shown to affect nearly 70-100% of cancer patients in previous studies.
    • It usually comes on suddenly, and does not result from activity or exertion. It is also not relieved by rest or sleep.
    • For this reason, it is a significant problem affecting patients, and can be debilitating and affect their daily physical and psychosocial functioning.
    • It often continues even after cancer treatment is complete.
  • The exact cause for CRF is unknown, and it is unclear whether it is related to the disease process or its treatments.
    • It has been proposed that cytokines or serotonin may be involved in causing CRF, although  this has not been proven.
  • Previous data by these authors on SSRIs (anti-depressants) for CRF had negative results.
  • Eugeroic agents are drugs with stimulating properties and no peripheral effects that have been hypothesized to improve symptoms of fatigue. One such agent is modafinil (or Provigil), which has been approved for use in certain sleep disorders.
  • This study was undertaken to examine the effects of Modafinil, an eugeroic agent, on the severity of CRF.
    • The objective of this study was to assess the degree to which modafinil can reduce fatigue in cancer patients receiving chemotherapy.
    • A secondary objective was to assess the relationship between depression and fatigue in patients treated with this drug.

Materials and Methods

  • This is a randomized, double-blinded, placebo-controlled, multicenter study. A total of 888 cancer patients undergoing chemotherapy from 23 centers were assessed for fatigue using a 10-point standard fatigue scale. 
    • Patients who scored >2 were eligible and randomly assigned to one of two arms. 
  • Other Eligibility criteria:
    • Patients who are concurrently receiving or have previously received chemotherapy, and are scheduled for at least 3 additional cycles of chemotherapy.
    • No concurrent radiotherapy or interferon therapy.
    • No prior modafinil.
  • Patients were randomized to either receive 200 mg modafinil orally once daily or an oral placebo drug once daily, starting on day 5 of the second cycle of chemotherapy. 
    • Treatment in both arms continued until day 7 of cycle 4 of chemotherapy.
  • Patient-reported depression, fatigue, sleepiness, and quality of life were assessed on day 7 of cycles 2 and 4 of chemotherapy using valid reliable measures.
  • Analysis of covariance testing was used to measure differences between treatment and control groups at cycle 4 adjusting for cycle 2. 

Results

  • 642 patients were randomized to the treatment group (n=320) or the control group (n=322). 
  • A significant positive effect on fatigue was found in the treatment group when compared to the control group (p=0.03), along with a significant interaction between treatment effects and fatigue noted at cycle 2. 
  • When data was analyzed by severity of fatigue, a higher level of improvement was seen in the treatment group for those with severe fatigue (score >6 on a 10 pt scale) at cycle 2 compared with the placebo group (p=0.04). 
    • But this effect was not seen for patients with mild or moderate baseline fatigue. The          p-values for patients with mild (0-4) or moderate (5-6) fatigue were 0.37 and 0.94, respectively. 
  • The treatment group reported significantly less sleepiness than the placebo group (p=0.002). 
  • There were no significant differences seen in terms of depression between the 2 groups (p=0.83).

Author's Conclusions

  • The eugeroic drug, modafinil, appears to have a significant effect in controlling CRF, especially in patients with severe baseline CRF. 
  • The drug caused a significant reduction in sleepiness, and therefore the dose used was appropriate to see an effect. It also assures us that the treatment was biologically active and works as advertised.
  • The drug effect is dependent on baseline fatigue level.
  • There is no effect on depression of this drug. 
    • It has been shown that Paxil has effects on depression, but not fatigue, and now this study shows that modafinil has effects on fatigue, but not depression. This allows us to hypothesize that the mechanisms for depression and fatigue in cancer patients are likely different. 

Clinical/Scientific Implications

  • Cancer-related fatigue is a debilitating symptom for cancer patients, and can affect these patients not only while they are receiving cancer treatment, but for years later as well. As of yet, there have not been many therapeutic agents which are effective in reducing CRF. 
  • This trial represents a well-designed, large phase III randomized study evaluating the effects of modafinil, an eugeroic agent, on cancer-related fatigue. It provides promising results, and may be very beneficial to patients suffering from CRF.
  • Although this study provided a positive result, the authors did not report toxicity data, and it is unclear from this report how safe and well-tolerated this drug is overall. This will be very important to see before we actually start implementing this treatment in the clinic for our cancer patients.
  • The authors were able to show an improvement in fatigue in the treatment arm compared to the control arm; however, this benefit was only seen in patients with severe fatigue (score>6). 
    • This begs the question as to whether or not future studies or the clinical use of this drug  should be limited only to those patients who report severe fatigue. Or should we use it prophylactically in all patients who report some level of fatigue? 
  • One significant limitation of this study is that the quantification of fatigue was done by patient self-reporting on a 10-point scale, which may not be very accurate and is very subjective. Functional status of patients during daytime hours or time spent sleeping per day may be other tools which can be used to measure fatigue in future studies. 
  • Although certain questions remain unanswered, this trial demonstrates a benefit to modafinil in patients suffering from severe CRF. The data may also help us to understand the mechanism for cause of CRF, so that new agents to treat this condition can be discovered and researched in future trials.

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