Assessment of neurocognitive impairment in patients with brain metastases

To determine the potential effect of cancer treatment on a patient’s pattern of cognitive strengths and weaknesses, objective assessment of cognitive functioning via comprehensive neuropsychological assessment is necessary. In determining whether a specific anticancer therapy is associated with risks or benefits to neurocognitive functioning, it is critical to have information regarding the presence and pattern of neurocognitive impairments before treatment. In patients with brain metastases, neurocognitive impairment is often evident before the initiation of therapies specifically aimed at treating the metastases; the nature and severity of such impairment may be influenced by lesion location, lesion momentum, and the untoward effect of tumor and edema on frontal-subcortical networks. In addition, patients may have already experienced alterations in neurocognitive functioning secondary to the untoward effect of their primary cancer and systemic therapies. In a small pilot study investigating neurocognitive impairment in patients with brain metastases, baseline impairment was observed on at least one test in 67% of the study population, with most impairment frequently observed on measures assessing executive functioning, motor dexterity, and learning and memory. In the absence of this baseline information, patients might have easily been misclassified as cognitively impaired or not impaired after treatment, and determination of change secondary to subsequent treatment would not have been feasible.

In addition to alterations in neurocognitive functioning secondary to tumors, specific treatments aimed at controlling brain metastases may lead to additional neurocognitive changes. For many years, whole brain radiotherapy (WBRT) was the standard treatment of brain metastases. Recent advances in treatment have revealed a survival benefit of surgery or stereotactic radiosurgery (SRS) plus WBRT over WBRT alone for patients with a single brain metastasis. Questions have since been raised regarding the potentially differential effect of these treatments on neurocognitive functioning, with concern that WBRT is potentially more neurotoxic and may even lead to radiation-induced dementia. One study found that WBRT may actually have a beneficial effect on specific aspects of neurocognitive functioning through a reduction in intracranial tumor burden; in this study, patients with a good radiologic response to WBRT showed improvement in performance on tests assessing executive functioning and fine motor dexterity. However, performance on memory testing was not significantly improved, even for those patients with a good radiographic response, and the investigators speculated that hippocampally mediated functions such as memory may be particularly vulnerable to WBRT. Evidence of differential neurotoxicity on memory systems was further demonstrated in a randomized controlled trial, which found that patients receiving SRS plus WBRT were significantly more likely to evidence a decline in learning and memory at 4 months after treatment than patients receiving SRS alone. As a result of the information provided by the inclusion of neurocognitive tests as an outcome measure, the investigators recommended that the initial treatment of brain metastases be limited to the use of SRS alone, with close clinical monitoring for recurrent brain metastases in an effort to preserve neurocognitive functioning for as long as possible.

In addition to providing information regarding potential neurotoxicities associated with treatment, neurocognitive evaluation offers a means to evaluate the effect of therapies that may be beneficial to neurocognitive function in that they may delay expected disease progression. For example, time to neurocognitive progression was prolonged in patients with brain metastases who were treated with WBRT plus motexafin gadolinium, as opposed to WBRT alone.

Assessment of QOL in patients with brain metastases

Although there is no universally accepted definition of QOL, it is generally agreed that QOL is a multidimensional construct encompassing patient perception of overall well-being. It is necessary to differentiate QOL from symptom assessment, because the perceived effect of a given symptom may vary significantly between individuals and over time. QOL data may serve to increase the awareness on variables that affect patient well-being, inform treatment decisions, and identify targets for intervention.

Similar to the assessment of neurocognitive functioning, assessment of patients’ QOL has been evolving over time. Historically, most studies used a rating of functional status determined by health care providers, such as the Karnofsky Performance Scale (KPS), as a proxy for QOL. Despite the limited reliability of this scale, which in one study was found to have interphysician agreement of only 29%, it remains the most common outcome measure used in the neuro-oncology literature. In fact, in a review of trials investigating the effect of WBRT on patients with brain metastases, 33 of the 55 trials used the KPS. The KPS, although valuable as a gross estimate of functional status, measures only one facet of the broader concept of QOL. A thorough assessment extending beyond functional status alone can enrich physicians’ understanding of patient QOL by increasing awareness of other key factors contributing to this outcome.

It must be acknowledged that there are challenges associated with assessing patients’ QOL. One of the greatest challenges is the possibility that functional impairment may affect an individual’s ability to complete self-report measures; the developers of the Functional Assessment of Cancer Therapy-Brain (FACT-BR), for example, noted that often only higher-functioning patients (KPS>60) are able to complete the questionnaire. Neurocognitive dysfunction may interfere with the patients’ ability to accurately complete self-report measures, especially as the disease progresses and cognitive impairment becomes increasingly problematic. Because of these challenges, the use of proxy ratings is inherently appealing, particularly because some patients with brain metastases may be unable to complete self-report measures. Some studies have attempted to garner greater outcome data by including standard measures completed by health care providers or caregiver ratings. However, these approaches are problematic because evidence suggests that patient QOL as rated by physicians and caregivers may be inaccurate. In one study investigating QOL ratings in patients with skull base tumors, surgeons overrated patients’ QOL in most cases and there was no significant correlation between patient and surgeon ratings at the individual level. Some data examining patient-caregiver agreement in QOL ratings were initially more encouraging. For example, one study found that substantial discrepancies occurred in only a small minority (5%–10%) of patient-caregiver pairs using the European Organization for Research into the Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). However, the investigators acknowledged that the rating agreement decreased as the patients’ level of physical and cognitive impairment increased, leaving questions regarding the reliability of proxy ratings for those who may need them most. In a study examining patient-caregiver agreement for patients with brain metastases, 60 patient-caregiver pairs completed the FACT-BR at baseline (before undergoing WBRT). Concordance between patient and proxy ratings was poor across all scales and could not be determined at follow-up secondary to high rates of attrition. These findings suggest that the use of proxy ratings to assess patient QOL should generally be avoided.

Given that proxy ratings are unlikely to yield consistently accurate information regarding a patient’s perceived well-being, the use of patient-reported outcomes has become increasingly recognized as the standard in QOL assessment. An ideal QOL measure can be completed by individuals who may be ill or have mild neurocognitive impairment, demonstrates reliability and validity, and taps patient perception of all relevant domains, including functional status, social well-being, cognitive symptoms, physical functioning, and emotional health. Although no perfect or universally applicable measure exists, numerous instruments have been developed in an effort to meet the need for QOL data in patients with cancer and several have been applied in patients with brain metastases.

One of the most commonly used QOL instruments is the FACT, a self-report instrument that provides information regarding patient’s perceptions of their physical, social, emotional, and functional well-being. An additional subscale addressing issues relevant to patients with brain tumors was also developed (FACT-BR) ; both the general scale and the brain subscale have been demonstrated to have good validity and reliability. In one study investigating the effect of WBRT on patient-rated QOL, a statistically nonsignificant mean deterioration in FACT-BR ratings was observed from baseline to 1 month. Similarly, a more recent study showed a trend toward worsening FACT-BR ratings at 2 months post-WBRT; some patients were unable to complete the questionnaire at the later time point secondary to significant health declines or death.

Other QOL measures have also indicated a decline in QOL after treatment of brain metastases. A recent pilot study used the EORTC QLQ-C30, a validated measure including domains assessing physical, cognitive, emotional, and social functioning, as well as global QOL, symptoms, and financial consequences. A shortened version of the questionnaire, the QLQ-C15-PAL, was also used. Combined data from these measures revealed relatively stable ratings of global QOL but declines in physical functioning, energy level, and appetite.

Although the above-mentioned studies suggest a trend toward declining QOL in association with WBRT for brain metastases, other studies yield a different finding. For example, a small study including 19 patients with brain metastases who had received surgery or radiosurgery for a solitary brain metastasis and who were randomized to receive WBRT versus observation found no difference in change from baseline in patient QOL ratings on the EORTC QLQ-C30. It is noted, however, that the analyses in this study included only the 2 global questions regarding overall health and QOL. Another study found significant improvement across all parameters measured by the EORTC QLC-C30, including global QOL, perceived physical,role, emotional, cognitive, and social functioning as well as improvement in many symptoms.