By William B. Ershler, MD
Synopsis: There has long been an appreciation of the risk of cognitive decline associated with chemotherapy but questions remain about the magnitude and duration of the observed deficits. In this meta-analysis of studies that included neuropsychological assessments at a minimum of 6 months after completion of breast cancer chemotherapy, definite but small deficits were found for both verbal and visuospatial capabilities. In this analysis, age and educational status were not found to be moderators of acquired deficits.
Source: Jim HSL, et al. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 2012;30:3578-3587.
Whereas there has been substantial research on the cognitive effects of chemotherapy, including prior meta-analyses,1-4 the issue remains unclear whether such treatment produces long-term deficits, and if so, how much. It remains well-established that moderate-to-severe cognitive impairment occurs in a substantial percent of chemotherapy-treated breast cancer patients (between 15% and 75%5,6). Yet, evidence is mixed regarding long-term cognitive deficits in patients treated with chemotherapy. Furthermore, some data now suggest that cognitive deficits may develop after the completion of treatment.7
Previous meta-analyses, the latest of which was published in 2006, were not focused specifically on the post-chemotherapy period, and since these publications there have been several reports providing additional information. Thus, Jim and colleagues performed the current meta-analysis, the goal of which was to assess cognitive functioning in breast cancer survivors who were treated with chemotherapy a minimum of 6 months prior to analysis.
The investigators, by searching PubMed and other major databases, found 2751 abstracts, and from these they found 17 studies that met stringent criteria for inclusion in this analysis. The 17 studies included 807 patients previously treated with standard-dose chemotherapy for breast cancer and on whom cognitive studies were performed 6 months or more after completion of chemotherapy. Neuropsychological tests were categorized according to eight cognitive domains: attention, executive functioning, information processing, motor speed, verbal ability, verbal memory, visual memory, and visuospatial ability.
Deficits in cognitive functioning were observed in patients treated with chemotherapy relative to controls or prechemotherapy baseline in the domains of verbal ability (g = -0.19; P < 0.01) and visuospatial ability (g = -0.27; P < 0.01). Patients treated with chemotherapy performed worse than non-cancer controls in verbal ability and worse than patients treated without chemotherapy in visuospatial ability (both P < 0.01). Age, education, time since treatment, and endocrine therapy did not moderate observed cognitive deficits in verbal ability or visuospatial ability (all P ≥ 0.51).
Results indicate that, on average, observed cognitive deficits in patients with breast cancer previously treated with chemotherapy are small in magnitude and limited to the domains of verbal ability and visuospatial ability. That the magnitude of observed deficits is small is reassuring, particularly when considering some of the fairly dramatic changes that have been reported for breast cancer patients actively receiving therapy. However, persistence of deficits 6 months and beyond raises concerns that such deficits might be long lasting, if not permanent.
One unexpected finding was that age and education status were not shown to moderate the effects of chemotherapy-induced cognitive change. However, the strength of this and other conclusions based on meta-analysis is only as robust as the studies examined in the analysis, and the authors acknowledged that there might not have been sufficient numbers of older or less-educated patients to demonstrate significant associations. In contrast, in one recent report,8 age and "cognitive reserve" (an attribute comprised of such factors as education, employment, and cognitive stimulation) were shown to be important factors predicting chemotherapy-associated decline. Thus, older patients with low levels of pretreatment cognitive reserve were found to be most vulnerable to post-treatment cognitive decline.
Another concern is that this, as with many of the reports of chemotherapy-associated brain deficits, focused on breast cancer patients only. Such patients often receive additional and somewhat complex treatment regimens that include surgery, radiation, and hormonal treatments, all of which may confound interpretation of observed findings. Thus, it would be premature to generalize these findings to chemotherapy treatment in general. Further, most of the primary studies on this topic exclude patients who might be at highest risk for cognitive decline, such as those with significant comorbidities, depression, or neurologic disorders. Thus, as highlighted by the accompanying editorial,9 the findings from this meta-analysis might significantly under represent the magnitude of the cognitive impact of cancer treatments.
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