Editorial Neurocognitive Impairment As One Facet of Cancer-Related Sickness

JNCI J Natl Cancer Inst (2015) 107(8): djv176

doi: 10.1093/jnci/djv176 First published online June 22, 2015 Editorial

editorial Neurocognitive Impairment as One Facet of Cancer-Related Sickness

Behavior Symptoms Downloaded from https://academic.oup.com/jnci/article/107/8/djv176/952001 by guest on 29 September 2021

Carissa A. Low, Pawel Kalinski, Dana H. Bovbjerg

Affiliation of authors: University of Pittsburgh Cancer Institute, Pittsburgh, PA (CAL, PK, DHB).

Correspondence to: Dana H. Bovbjerg, PhD, Hillman Cancer Center, Suite 140, 5115 Centre Avenue, Pittsburgh, PA 15232-1301 (e-mail: [email protected]).

Cancer-related cognitive impairment (CRCI) is now widely rec- Strong support for causal links between tumor growth and ognized as a significant clinical problem that can negatively cognitive deficits in the host is beginning to emerge from pre- impact quality of life for many survivors long after completion clinical research that has demonstrated effects of both experi- of curative treatments (1,2). Less well appreciated is accumu- mentally induced and transplanted tumors on well-established lating evidence that CRCI exists prior to initiation of chemo- behavioral tests of cognitive function in rat and mouse models therapy. Emerging research strongly suggests that the common (4–7). In one such study, tumor-induced memory impairment characterization of this phenomenon as “chemobrain” is a mis- was found to be accompanied by increased expression of hip- nomer and highlights the need for new conceptualizations of pocampal TNFa mRNA in the brain (though not upregulation in the underlying mechanisms, which can then be targeted for peripheral plasma TNFa). Interestingly, mice bearing tumors in intervention. that study also developed increases in depression-like behavior, In this issue of the Journal, Patel and colleagues examined as well as higher plasma levels of the stress-related hormone the relationship between neurocognitive performance on corticosterone (7). This and other preclinical observations sug- standardized tests and circulating proinflammatory cytokine gest that the effects of cancer on cognitive function might best levels in newly diagnosed breast cancer patients (3). In their be considered from the perspective of the broader literature on sample of 174 postmenopausal patients, higher plasma lev- “sickness behavior” symptoms in cancer (8). Sickness behavior els of sTNF-RII (used as a marker of TNFa production) were symptoms include cognitive impairments, but also depressive associated with poorer memory performance. Relative to 88 symptoms, fatigue, pain sensitization, and sleep disturbances, age-matched control patients, newly diagnosed breast can- among others (Figure 1). These symptoms often cluster together cer patients demonstrated impaired verbal memory perfor- in cancer patients over time and have been correlated with mance (but not impaired executive functioning or processing circulating inflammatory cytokines 9( ), with causal evidence speed) and had higher levels of IL-1ra (but not sTNF-RII or from animal and human experimental studies that inflamma- IL-6). While several previous investigations have examined tory stimuli can trigger these behavioral changes (8). Sickness cognitive function prior to adjuvant cancer treatment, Patel behavior symptoms reflect an evolutionarily adaptive motiva- and colleagues are the first to examine neurocognitive perfor- tional state in which rest and recovery are prioritized over other mance in breast cancer patients prior to any cancer treatment biological functions. While Patel et al. adjusted for fatigue and (including surgery). Patel and colleagues adjusted their statis- anxious mood in their analyses, they did not assess depressive tical models for a number of key factors that may predict neu- symptoms or sleep disturbance, both of which are common in rocognitive performance, including age, education, fatigue, the immediate aftermath of a cancer diagnosis. Future research and, importantly, comorbid medical conditions such as dia- that considers the broad constellation of behavioral symptoms betes or hypertension, which are common in older people but related to inflammation rather than focusing on single symp- are infrequently considered as possible contributors to CRCI. toms such as neurocognitive performance may help to clarify Their results suggest that elevations in proinflammatory whether interrelated neurovegetative symptoms have distinct cytokines (eg, TNFa) elicited by the underlying disease may biological mechanisms (10,11). be sufficient to cause decrements in memory performance. Cancer-related stress is another psychological process Given the correlational approach used in this initial clinical that was not considered in the study by Patel and colleagues. study, as the authors note, one cannot rule out the contri- A recent paper in the Journal reported that posttraumatic stress bution of additional factors (eg, diet, medications, physical symptoms related to cancer accounted for differences in cog- activity) that were not assessed. nitive function between breast cancer patients (assessed prior

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Figure 1. Sickness behavior symptoms model. to chemotherapy) and control patients (12). In newly diagnosed engagement with the regulatory circuitry linking the brain and cancer patients, acute psychological stress is often elevated the immune system (20). Physical exercise has broad psycho- as patients undergo staging and other medical testing, make logical and physiological benefits, including improvements in treatment decisions, cope with current or anticipated physi- cognition and brain function in aging adults (21), reductions cal symptoms, and grapple with existential concerns. These in fatigue and depressive symptoms in cancer patients and stressors may not only affect performance on neurocognitive survivors (22), and reductions in inflammatory biomarkers (23). tests but may themselves activate proinflammatory pathways Given emerging evidence that exercise may also increase the (13). Indeed, psychological stress may interact with inflamma- efficacy of chemotherapy by reducing tumor hypoxia (24), exer- tory pathways to synergistically increase cognitive changes and cise in the context of active cancer treatment may be especially other behavioral symptoms (14). Psychological stress may also beneficial. Because exercise has been demonstrated to reduce have direct effects on the central nervous system, including both the biological mechanisms of sickness behavior symp- decreases in neurogenesis and hippocampal volume (15), that toms (eg, inflammation) and the symptoms themselves with could be exacerbated by additional biological insults of cancer minimal side effects, exercise interventions may dramatically and its treatment. These potential interactions between psy- alter the trajectory of cancer-related neurocognitive impair- chological and physiological reactions to cancer warrant further ments. This hypothesis requires testing in randomized control research. trials. With regard to potential interventions to reduce CRCI and The innovative study by Patel and colleagues in the Journal other sickness behaviors, peripheral blockade of TNF (eg, with points the way to important areas for future longitudinal, trans- infliximab) would have to be used with considerable cau- lational, and intervention research. These multidisciplinary tion given the important and complex role of TNF in tumor efforts will improve basic scientific understanding of how acti- immune surveillance (16,17). Additional options may include vation of proinflammatory cytokine networks by cancer cells targeting IL-1 and IL-6, both known to promote Th17 immu- may increase behavioral symptoms and will also guide clinical nity (18), involved in multiple aspects of neuropathology (19). interventions to reduce these cancer-related symptoms and A behavioral intervention might offer hope of a more nuanced improve patient quality of life. 3 of 3 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 8

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