Fatigue is the most common, and one of the most devastating, symptoms in patients with cancer.¹ It has been defined as “a distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or cancer treatments that is not proportional to recent activity and interferes with usual functions.”²

Unfortunately, there are limited treatment options to alleviate this distressing symptom.^3,4 This is partly because fatigue is a complex, multidimensional syndrome. In recent years, there has been a much better understanding of the multiple mechanisms contributing to the expression of fatigue by patients with cancer. Tumor byproducts and host cytokines, direct effects of radiation therapy and chemotherapy, cachexia, deconditioning, opioids and other drugs, hypogonadism, metabolic abnormalities, chronic infection, mood abnormalities such as anxiety and depression, cognitive changes, and severe anemia are all contributors to the intensity of fatigue in patients with cancer.^4,5 In a given patient, it is quite likely that multiple mechanisms coexist at any given time and that the main contributors change as the disease progresses or as patients reach the completion of therapy.⁶

Ultimately, fatigue is a symptom, and therefore, it is perceived in the brain. For this reason, centrally acting agents have been among the most commonly tried for the management of fatigue. A recent systematic review concluded that methylphenidate was the agent for which the most research and supportive evidence exists.⁴ In this issue of Journal of Clinical Oncology, Moraska et al⁷ publish the results of a randomized, controlled trial, comparing a long-acting methylphenidate preparation versus a placebo in patients with cancer-related fatigue (CRF). The authors found no significant differences in usual fatigue, current fatigue, or worse fatigue during the course of the 4-week study. They did observe that patients with more advanced disease showed a significant response to methylphenidate as well as a trend for patients with more severe fatigue to improve more when receiving methylphenidate than when receiving placebo. Our group recently conducted a secondary review of patients who received methylphenidate in our clinical trials. Consistent with the results reported by Moraska et al, we observed that higher levels of fatigue were predictors of response to methylphenidate in patients with advanced cancer.⁸

The results of this study are consistent with those of a previous randomized, controlled trial by our group using an immediate-release methylphenidate preparation.⁹ However, there are some differences in the findings between our study and that of Moraska et al. Our study found a dramatic improvement in fatigue in both the methylphenidate and placebo groups, with no significant difference between the two arms.⁸ Moraska et al⁷ saw a less dramatic improvement in fatigue in both arms. One of the differences in these two studies is that patients in our study received regular phone calls from nurses for the assessment of their symptoms, and this may have had a major symptomatic effect. The difference in overall fatigue improvement between these two studies suggests that further research on interventions, such as phone calls or visits from nurses, should be conducted for CRF. The finding in these two studies emphasizes the importance of a placebo arm in all clinical trials on CRF.

Moraska et al⁷ observed significantly higher levels of nervousness and anorexia in the methylphenidate group as compared with the placebo group. Our randomized, controlled trial and our previous pilot, open label study—both using immediate-release methylphenidate—found no increase in any of these two adverse effects.^8,9 There was actually a trend toward improvement of these symptoms. This might be due to either the type of methylphenidate preparation or the fact that our patients received a slightly lower dosage. A meta-analysis of studies on both short- and long-term acting methylphenidate for the treatment of attention-deficit/hyperactivity disorder found a higher frequency of anorexia among patients receiving long-acting methylphenidate.¹⁰ More research is needed to better characterize the best type and dosage of this agent.

The study by Moraska et al⁷ suggests that some specific subgroups of patients might benefit from centrally acting agents such as methylphenidate. Unfortunately, we do not know who those patients may be. Methylphenidate has been found to be effective in reducing sedation in patients receiving opioids,¹¹ in the management of depression,¹² and in cognitive changes associated with brain tumors.¹³ It is possible that methylphenidate could be particularly effective for patients in whom these are major contributors to fatigue.

Where do we go from here? Fatigue is a complex multidimensional symptom, and it is therefore unlikely to be successfully managed with single pharmacologic or nonpharmacologic interventions. Patients are likely to require a combination of counseling, increased physical activity, correction of hormonal and metabolic abnormalities, and pharmacologic interventions aimed at body composition, inflammation, and brain function.

One of the biggest limitations in conducting research in CRF is the lack of an appropriate staging system. For clinical trials, the term “cancer-related fatigue” allows the inclusion of patients with dramatically different mechanisms, and this makes interpretation of the results of studies difficult.

The investigators in the current study⁷ and most other studies have used well-defined and reproducible criteria for eligibility. However, there is still a large heterogeneity in patient population with regard to the presence or intensity of the major contributors to fatigue.

One of the primary contributions to the effective treatment of most cancers was the development of a common language, based initially on histology and anatomic distribution and more recently on different blood- and tumor-cell markers. This allowed for the development and testing of combined and multimodal interventions. Such common language is currently lacking for fatigue and most cancer-related symptoms.

Future studies will need to better characterize the patient population and eligibility criteria based on the currently known and emerging contributors to fatigue. This will make it possible to test combined therapies, including pharmacologic and nonpharmacologic interventions. Novel statistical approaches such as Bayesian analysis will make it possible to test the independent or synergistic contributions of different interventions in the same group of patients. Ultimately, the best intervention for CRF will be the development of a personalized treatment plan based on the identification of the main contributing factors to fatigue in a given patient followed by evidence-based combined therapies.

One more important contribution of this study by Moraska et al⁷ is that it demonstrates that clinical trials of agents for the management of fatigue can be successfully completed by cooperative clinical trial groups. This is of great importance for the development of a body of knowledge on supportive and palliative interventions for patients with cancer.

source:JCO