As part of Cancer Network’s coverage of the 21st Annual Scientific Meeting of the Society for Neuro-Oncology, held November 17–20 in Scottsdale, Arizona, we spoke with neuro-oncologist David Cachia, MD, MRCP, an associate professor at the Medical University of South Carolina Hollings Cancer Center’s Brain & Spine Tumor Program. Dr. Cachia answered our questions about glioma-associated fatigue and cognitive dysfunction.

-Interviewed by Bryant Furlow

Cancer Network:How common are pronounced glioma-associated fatigue or neurocognitive dysfunction?

Dr. Cachia: Cancer-related fatigue is a common problem in most cancer patients with patients in some studies reporting fatigue as the most distressing symptom they perceive. In a clinical trials setting, reported prevalence rates range between 70% and 80% of patients. It is important to note that cancer-related fatigue differs from “normal” fatigue in that it tends to be more severe and distressing, frequently impacting the patient’s lifestyle and is less likely to be relieved by rest.

Similarly, in gliomas, fatigue is an extremely common problem. In one study, 96% of patients with high-grade gliomas reported moderate to severe fatigue. In another study, up to 80% of patients receiving radiation reported fatigue. Fatigue seems to persist even after treatment with a study looking at fatigue in patients with low-grade gliomas more than 3 years out from completion of treatment showing that 39% of patients more than 8 years from completion of treatment, still reporting severe fatigue. It is important to remember that fatigue fluctuates throughout the clinical course and as such it is important to monitor patients frequently. Most of our patients will at some point in their clinical course develop moderate to severe fatigue and as such this should be addressed.

Neurobehavioral symptoms are common in primary brain tumor patients, are frequently multiple, and are caused by a variety of factors. About one-third of patients with primary brain tumors experience clinically significant depression and anxiety while 30% to 73% of patients are affected by psychological distress.

Cancer Network: How common are extreme glioma-associated psychiatric problems like psychosis or hallucinations?

Dr. Cachia: Studies looking at hallucinations and psychosis in this patient population are very limited, mostly limited to case reports. It is rare for brain tumors to present with hallucinations or psychosis as the only presenting symptoms. There is some evidence to support the fact that surgery of brain tumors in certain locations (more specifically mesial temporal lobe) can trigger psychosis. Seizures originating from this area of the brain can also be the cause of psychosis. It is important to remember that medications commonly used in glioma patients-steroids and antiepileptic medications-can themselves induce psychosis.

Cancer Network:Do other neurocognitive dysfunctions result from the glioma per se, or from its treatment-or both?

Dr. Cachia: Many clinical and demographic factors are known to contribute to neurocognitive outcome differences in glioma patients.

Location: Patients with brain tumors involving the dominant hemisphere tend to have more cognitive deficits than patients with tumors involving the nondominant hemisphere.

Histology: Grade IV gliomas exhibit greater difficulty with verbal learning, processing speed, executive functioning, and language than grade II or III tumors.

Effects of treatment: Though immediate postoperative cognitive declines have been documented in surgical series, most of these deficits tend to resolve over time especially in low-grade glioma patients. Though radiation is well known to cause cognitive decline, studies in low-grade gliomas have shown that tumor and other treatment factors might be important contributing factors and more attention to address these factors might be pertinent.

Pre-illness functioning level [also matters].

Cancer Network:Are some patients more likely to develop these problems, than others? Are there particular risk factors other than tumor location and grade that can help to predict which patients are most likely to suffer cognitive dysfunction?

Dr. Cachia: In a study analyzing risk factors for the development of fatigue in 201 PBT [primary brain tumor] patients, female sex, poor performance status, and having active disease were the strongest predictors of fatigue. Women were 2.5 times more likely to develop severe fatigue than men. Patients with poor performance status were six times more likely to report moderate to severe fatigue while those on active treatment more than twice as likely to develop severe fatigue. Patients reporting moderate to severe fatigue are also much more likely to have other symptoms such as pain, distress, drowsiness, and weakness. This association between different symptoms is called symptom clustering and makes diagnosis of fatigue more difficult.

The relationship between histologic tumor grade and fatigue remains unclear with some studies finding an association between severity of fatigue and higher grade tumors whilst others did not.

Cancer Network:Are these problems treated among patients with glioma in the same way they would be for noncancer patients with similar problems, or does glioma pose particular challenges to symptoms management?

Dr. Cachia: The evidence on how to treat fatigue in primary brain tumor patients is unclear due to the limited number of studies evaluating this. This is surprising given how common fatigue is in this patient population. In a recent Cochrane meta-analysis, only one study met the inclusion criteria. Unfortunately, this study that randomized patients to receive either modafinil, a stimulant drug, versus placebo was hampered by problems in recruiting patients and 32% of the patients dropping out of the study. The results showed that modafinil and placebo both improved fatigue and cognitive function indicating a placebo effect with no difference between the two groups on improving fatigue.

Level 1 evidence exists for the treatment of cancer-related fatigue in patients on active treatment with exercise, yoga, massage, and psychosocial interventions, but whether this can be extrapolated to primary brain tumor patients is unclear since most of the studies on which these recommendations are based upon included solid tumor patients, more specifically breast cancer patients with a very limited number of primary brain tumor patients if any.

Cancer Network:Are there noteworthy investigational treatments in development or on the horizon, that might help to better manage these problems?

Dr. Cachia: With a greater recognition of the impact that fatigue has on quality of life of these patients, more trials are now including fatigue and health-related quality-of-life measures as primary or secondary endpoints. Research is also ongoing to better understand the underlying pathophysiology of fatigue. A recent presentation at ASCO [American Society of Clinical Oncology] seems to indicate genetic polymorphisms involved in maintaining the circadian clock mechanism as potentially contributing to the development of fatigue. Only by learning more about the pathophysiology and characterization of its underlying biology will we be able to develop appropriate therapies.

A phase III trial is evaluating the use of armodafinil to treat fatigue in glioma patients whilst another is looking at dexamfetamine sulfate. Nonpharmacologic interventions are also being evaluated and in the next few years we might know more and have better tools at our disposal to help patients with fatigue.