Joanna E. Fardell

Neurobiological basis of chemotherapy-induced cognitive impairment: A review of rodent research

For some cancer survivors chemotherapy treatment is associated with lasting cognitive impairment, long after treatment cessation. Several candidate mechanisms have been suggested, yet clinical research has been unable to clearly tease apart these hypotheses. Rodent research has allowed a systematic study of these underlying mechanisms in the absence of potential patient confounds. Herein, this research is reviewed with emphasis on the role of the blood-brain barrier, neurogenesis, oxidative stress, white matter, immune system/(neuro) inflammation, HPA axis, blood flow, and cancer in chemotherapy-induced cognitive impairment. Furthermore, potential pharmacotherapy and behavioral intervention strategies are reviewed. This paper ends with methodological considerations in study of chemotherapy and cognition.

Chemotherapy and Cognitive Impairment: Treatment Options

Chemotherapy has improved survival rates in patients with many of the common cancers. However, there is reliable evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for many years after the completion of chemotherapy. The etiology of this phenomenon is largely unknown, and currently there are no proven treatments. This article explores the clinical and preclinical literature on potential therapies for chemotherapy‐induced cognitive impairments. Emerging results suggest that both pharmacological and behavioral approaches may offer patients some benefits. However, research in this area has been limited and is sometimes fraught with methodological flaws. As a result, it is difficult to draw definite conclusions regarding treatment efficacy. These issues, along with predictors of cognitive decline, are discussed in the light of possible interventions.

The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats.

Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V1aR) pharmacology and regional patterns of c‐Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus‐maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c‐Fos expression. Results showed that WAY 267,464 had higher affinity (Ki) at the V1aR than the OTR (113 versus 978 nm). However, it had no functional response at the V1aR and only a weak functional effect (EC50) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V1aR antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V1aR (503 nm), with a functional EC50 of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V1aR agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c‐Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c‐Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V1aR. Antagonism of the V1aR by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences.

Fear of cancer recurrence: a theoretical review and novel cognitive processing formulation

PurposeFear of cancer recurrence (FCR) is prevalent among survivors. However, a comprehensive and universally accepted theoretical framework of FCR to guide intervention is lacking. This paper reviews theoretical frameworks previously used to explain FCR and describes the formulation of a novel theoretical framework for FCR.MethodsA systematic review of the literature was undertaken to identify conceptual frameworks or theories applied to FCR. MEDLINE, PubMED, CINAHL, AMED, PsycINFO and Web of Science were searched. Identified conceptual frameworks were reviewed for strength of evidence supporting their validity.ResultsOf 558 papers initially identified, 16 made reference to six different conceptual frameworks relating to FCR. The most comprehensive and evidence-based theoretical approach is the Common Sense Model (CSM). Other approaches have limited evidence supporting their application to FCR. Two theoretical approaches developed in the context of emotional disorders that appear to be highly relevant to FCR: the Self-Regulatory Executive Function (S-REF) model and Relational Frame Theory were combined with the CSM to produce a novel cognitive processing account of FCR.ConclusionsFew conceptual frameworks have been used consistently to guide FCR research, and not all frameworks are empirically well supported, suggesting that further discussion regarding the conceptualisation of FCR is needed. The novel theoretical framework for FCR presented highlights the multidimensional nature of FCR and the importance of cognitive processing and metacognitions in the development and maintenance of FCR.Implications for Cancer SurvivorsThe novel theoretical formulation of FCR outlined here provides a much-needed comprehensive framework to further investigate and address FCR in cancer survivors.

Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents.

Clinical studies have suggested that cognitive impairment due to chemotherapy persists long after treatment cessation. While animal studies have similarly found impairments in cognition due to chemotherapy, these studies are limited as they only assess the acute or extremely short-term effects of chemotherapy on cognition (e.g. within 1month of treatment). Male hooded Wistar rats (N=22) received either a high dose of methotrexate (MTX: 250mg/kg i.p.) or physiological saline. Cognitive performance was evaluated acutely at 2weeks, and up to 8months post injection using the Morris water maze, Novel object recognition task, and an instrumental go/no-go task to assess discrimination learning. MTX-treated rats displayed impaired novel object recognition compared to controls at 11, 95, and 255days after treatment. MTX rats were able to learn the hidden spatial location of a platform 22days after treatment. When tested again after a 95-day retention interval, MTX rats showed impaired spatial memory compared to controls, but were subsequently able to re-learn the task. Finally, MTX-treated rats showed considerable difficulty learning to inhibit their behaviour in an instrumental discrimination task. These results show that chemotherapy produces persistent but subtle cognitive deficits in laboratory rodents that vary with time post treatment.

The sum of all fears: conceptual challenges with measuring fear of cancer recurrence

Fear of cancer recurrence (FCR) is increasingly recognised as a major concern for people with cancer once active treatment is completed. Several instruments have been designed to assess FCR; however, no gold standard has emerged. Many instruments conceptualise FCR as a multidimensional construct. However, this potentially conflates FCR as an outcome with its antecedents and consequences. This is problematic when an aggregate of distinct dimensions is calculated, as is commonly recommended. For example, the total score on the Fear of Cancer Recurrence Inventory is an aggregate of items from seven sub-scales: triggers, severity, psychological distress, coping strategies, functioning impairments, insight and reassurance. Similarly, the total score on the Fear of Progression Questionnaire is an aggregate of affective reaction, partnership/family, work and loss of autonomy. Arguably, the severity and affective reaction domains represent fear, and the other sub-scales represent related concepts, rather than “dimensions” of FCR. The total score represents a combination of concepts whose meaning is unclear. The same total score could be produced by patients with very different experiences, and patients with the same level of fear could have very different total scores. Therefore, we argue that although the level of FCR may be determined by a complex network of antecedents and modifiers and have variable consequences, FCR itself may be a simple concept, which can be assessed using a smaller number of items. Conceptual clarity in its research infancy should prevent FCR becoming a construct that is vaguely operationalised and interpreted.

The short and long term effects of docetaxel chemotherapy on rodent object recognition and spatial reference memory

AIMS Previous animal studies have examined the potential for cytostatic drugs to induce learning and memory deficits in laboratory animals but, to date, there is no pre-clinical evidence that taxanes have the potential to cause cognitive impairment. Therefore our aim was to explore the short- and long-term cognitive effects of different dosing schedules of the taxane docetaxel (DTX) on laboratory rodents. MAIN METHODS Healthy male hooded Wistar rats were treated with DTX (6 mg/kg, 10mg/kg) or physiological saline (control), once a week for 3 weeks (Experiment 1) or once only (10mg/kg; Experiment 2). Cognitive function was assessed using the novel object recognition (NOR) task and spatial water maze (WM) task 1 to 3 weeks after treatment and again 4 months after treatment. KEY FINDINGS Shortly after DTX treatment, rats perform poorly on NOR regardless of treatment regimen. Treatment with a single injection of 10mg/kg DTX does not appear to induce sustained deficits in object recognition or peripheral neuropathy. SIGNIFICANCE Overall these findings show that treatment with the taxane DTX in the absence of cancer and other anti-cancer treatments causes cognitive impairment in healthy rodents.

Pilot of a theoretically grounded psychologist-delivered intervention for fear of cancer recurrence (Conquer Fear)

Dear Editor,IntroductionFear of cancer recurrence (FCR), defined as the fear orworry that cancer could return or progress in the sameplace or another part of the body [1], is a commonand debilitating problem among cancer survivors. A re-cent systematic review found that across different cancersites and assessment strategies, the following on aver-age: 73% of cancer survivors report some degree ofFCR (range=39–97%); 49% report moderate to highFCR (range=22–87%); and 7% report high FCR(range=0–15%) [2]. FCR is stable over time and hasbeen shown to impact negatively on quality of life(QOL), psychological adjustment, emotional distressand anxiety, ability to establish future plans and carerQOL [2]. High FCR has also been associated withgreater medical service usage and costs [2]. Despitethe high prevalence, morbidity and potential cost ofFCR, survivors commonly report strong unmet needsfor help managing FCR [2]. This suggests many cancerservices are currently providing inadequate care in thisarea. Indeed, clinicians in psycho-oncology report diffi-culties dealing with high FCR [3]. There is a clear needfor interventions specifically targeting FCR, but veryfew have been developed and evaluated to date [4–6].This paper reports on the pilot testing of a novel, theo-retically based intervention for FCR.MethodsInterventionThe manualised intervention (Conquer Fear) aims to re-duce the impact of FCR and is based on the common-sense model (CSM) of illness [7], self-regulatory execu-tive function (S-REF) model [8] and Relational FrameTheory (RFT) [9]. Key intervention objectives includethe following: (a) teaching strategies for controllingworry and excessive threat monitoring (S-REF), (b)modifying unhelpful beliefs about worry (S-REF), (c)developing appropriate monitoring and screeningbehaviours (CSM), (d) providing information aboutfollow-up care and empirically supported behaviouralchange (e.g. weight loss and exercise) to reduce riskof recurrence (CSM), (e) addressing cancer-related exis-tential changes (RFT), and (f) promoting values-basedgoal-setting (RFT). The intervention comprises five60–90 min, individual face-to-face sessions with atrained psychologist/psychiatrist (therapist). Home-basedpractice and reading (≈2 h/week) is encouraged to con-solidate skills. See Table 1 for an overview of sessioncontent. More details are provided in Butow et al. [10].Study designThe feasibility, acceptability and likely efficacy ofConquer Fear were evaluated in a small longitudinalsingle-arm pilot study approved by relevant local ethicscommittees.

The impact of sustained and intermittent docetaxel chemotherapy regimens on cognition and neural morphology in healthy mice

RationaleA subset of cancer survivors demonstrates impairments in cognition long after chemotherapy completion. At present, it is unclear whether these changes are due to direct neurotoxic effects of chemotherapy.ObjectivesThis study examined the impact of variable docetaxel (DTX) chemotherapy dosing on brain DTX exposure via analyses of neural morphology and changes in cognition.MethodsMale CD-1 mice were treated with DTX either intermittently (8 mg/kg i.p. weekly) or via a sustained delivery system (DTX-PoLigel), which continuously releases DTX. Both groups received total DTX doses of 32 mg/kg. Mice were assessed on the novel object recognition (NOR) task and the Morris water maze (MWM) shortly after treatment.ResultsPost-treatment behavioral testing demonstrated impaired NOR in mice treated with either dosing schedule relative to controls. No differences were observed between groups in MWM training and initial testing, though control mice performed better than chance while DTX-treated mice did not. Appreciable amounts of DTX were found in the brain after both treatment regimens. DTX treatment did not significantly increase levels of apoptosis within the CNS. However, some elevation in neural autophagy was observed following DTX treatment. Analysis of astrocytic activation demonstrated that intermittent DTX treatment resulted in an elevation of GFAP-positive astrocytes for 48 h after administration. Sustained chemotherapy demonstrated prolonged but lower levels of astrocyte activation over 9 days following implantation.ConclusionsDTX treatment induced cognitive impairment shortly after treatment. Further, these findings suggest an association between DTX dosing, neurotoxicity, and cognitive effects.

Participation in psychosocial oncology and quality-of-life research: a systematic review

Quality-of-life and psychosocial oncology studies that have low participation might have less precision, less statistical power, and can have non-response bias. In this systematic Review, we searched MEDLINE, Embase, and PsycInfo, for paediatric studies published in 2010-15 and adults studies published 2014-15. Studies were eligible if they were original studies published in a peer-reviewed journal; recruited children (aged 0-18 years at diagnosis) with cancer or their parents, or adult patients with cancer; and assessed psychosocial outcomes, including quality of life, depression, anxiety, wellbeing, distress, coping, or adjustment as a primary or secondary outcome. We assessed participation reporting quality, calculated percentages of participation achieved, and measured the influence of study design and participant characteristics. We reviewed 311 studies including a total of 87 240 adults, children, and parents. Mean participation across studies was more than 70% (paediatric participation was 72% and adult participation was 74%). Many studies did not report data essential for the assessment of participation, especially for non-respondents. Studies using a longitudinal cohort design had higher participation than randomised trials. In paediatric studies, recruitment of participants at diagnosis, face to face, and with the use of short questionnaires yielded higher participation. Other study design characteristics (method of data collection, who enrolled the participants, and incentives) and patient characteristics (cancer type, patient or parent age, and sex) did not affect participation in either paediatric or adult studies. Researchers can use these data to improve reporting quality and make evidence-based choices to maximise participation in future studies.