As the population of cancer survivors has grown into the millions, there has been increasing emphasis on understanding how the late effects of treatment affect survivors' ability to return to work ...school, their capacity to function and live independently, and their overall quality of life. This review focuses on cognitive change associated with cancer and cancer treatments. Research in this area has progressed from a pharmacotoxicology perspective to a view of the cognitive change as a complex interaction of aspects of the treatment, vulnerability factors that increase risk for posttreatment cognitive decline, cancer biology, and the biology of aging. Methodological advances include the development of (
a
) measurement approaches that assess more fine-grained subcomponents of cognition based on cognitive neuroscience and (
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) advanced statistical approaches. Conceptual issues that arise from this multidimensional perspective are described in relation to future directions, understanding of mechanisms, and development of innovative interventions.
Cognitive changes associated with cancer and cancer treatments have become an increasing concern. Using breast cancer as the prototype, we reviewed the research from neuropsychological, imaging, ...genetic, and animal studies that have examined pre- and post-treatment cognitive change. An impressive body of research supports the contention that a subgroup of patients is vulnerable to post-treatment cognitive problems. We also propose that models of aging may be a useful conceptual framework for guiding research in this area and suggest that a useful perspective may be viewing cognitive change in patients with cancer within the context of factors that influence the trajectory of normal aging.
The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the ...development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatment-induced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/or have independent effects on cognitive function.
Abstract
This review summarizes the current literature on cancer-related cognitive impairment (CRCI) with a focus on prevalence, mechanisms, and possible interventions for CRCI in those who receive ...adjuvant chemotherapy for non-central nervous system tumours and is primarily focused on breast cancer. CRCI is characterized as deficits in areas of cognition including memory, attention, concentration, and executive function. Development of CRCI can impair quality of life and impact treatment decisions. CRCI is highly prevalent; these problems can be detected in up to 30% of patients prior to chemotherapy, up to 75% of patients report some form of CRCI during treatment, and CRCI is still present in up to 35% of patients many years following completion of treatment. While the trajectory of CRCI is becoming better understood, the mechanisms underlying the development of CRCI are still obscure; however, host characteristics, immune dysfunction, neural toxicity, and genetics may play key roles in the development and trajectory of CRCI. Intervention research is limited, though strategies to maintain function are being studied with promising preliminary findings. This review highlights key research being conducted in these areas, both in patient populations and in animals, which will ultimately result in better understanding and effective treatments for CRCI.
Randomized controlled trials have supported integrated oncology and palliative care (PC); however, optimal timing has not been evaluated. We investigated the effect of early versus delayed PC on ...quality of life (QOL), symptom impact, mood, 1-year survival, and resource use.
Between October 2010 and March 2013, 207 patients with advanced cancer at a National Cancer Institute cancer center, a Veterans Affairs Medical Center, and community outreach clinics were randomly assigned to receive an in-person PC consultation, structured PC telehealth nurse coaching sessions (once per week for six sessions), and monthly follow-up either early after enrollment or 3 months later. Outcomes were QOL, symptom impact, mood, 1-year survival, and resource use (hospital/intensive care unit days, emergency room visits, chemotherapy in last 14 days, and death location).
Overall patient-reported outcomes were not statistically significant after enrollment (QOL, P = .34; symptom impact, P = .09; mood, P = .33) or before death (QOL, P = .73; symptom impact, P = .30; mood, P = .82). Kaplan-Meier 1-year survival rates were 63% in the early group and 48% in the delayed group (difference, 15%; P = .038). Relative rates of early to delayed decedents' resource use were similar for hospital days (0.73; 95% CI, 0.41 to 1.27; P = .26), intensive care unit days (0.68; 95% CI, 0.23 to 2.02; P = .49), emergency room visits (0.73; 95% CI, 0.45 to 1.19; P = .21), chemotherapy in last 14 days (1.57; 95% CI, 0.37 to 6.7; P = .27), and home death (27 54% v 28 47%; P = .60).
Early-entry participants' patient-reported outcomes and resource use were not statistically different; however, their survival 1-year after enrollment was improved compared with those who began 3 months later. Understanding the complex mechanisms whereby PC may improve survival remains an important research priority.
Abstract Context Although cognitive impairments have been identified in patients with non–central nervous system cancer, especially breast cancer, the respective roles of cancer and therapies, and ...the mechanisms involved in cognitive dysfunction remain unclear. Objectives To report a state-of-the-art update from the International Cognitive and Cancer Task Force conference held in 2012. Methods A report of the meeting and recent new perspectives are presented. Results Recent clinical data support that non–central nervous system cancer per se may be involved in cognitive dysfunctions associated with inflammation parameters. The role of chemotherapy on cognitive decline was confirmed in colorectal and testicular cancers. Whereas the impact of hormone therapy remains debatable, some studies support a negative impact of targeted therapies on cognition. Regarding interventions, preliminary results of cognitive rehabilitation showed encouraging results. The methodology of future longitudinal studies has to be optimized by a priori end points, the use of validated test batteries, and the inclusion of control groups. Comorbidities and aging are important factors to be taken into account in future studies. Preclinical studies in animal models highlighted the role of cancer itself on cognition and support the possible benefits of prevention/care during chemotherapy. Progress in neuroimaging will help specify neural processes affected by treatments. Conclusion Clinical data and animal models confirmed that chemotherapy induces direct cognitive deficit. The benefits of cognitive rehabilitation are still to be confirmed. Studies evaluating the mechanisms underlying cognitive impairments using advanced neuroimaging techniques integrating the evaluation of genetic factors are ongoing.
To prospectively examine alterations in working memory (WM) -associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging.
Patients treated with ...chemotherapy (CTx+; n = 16) or without chemotherapy (CTx-; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx- and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001.
At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx-), with prominent alterations in the frontal lobes bilaterally.
Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.
To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments.
Patients with breast cancer exposed to chemotherapy ...(n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals.
Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group.
These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen.
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