Assessing chemotherapy-induced peripheral neuropathy with patient reported outcome measures: a systematic review of measurement properties and considerations for future use.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of cancer treatment, with potential to significantly impact cancer survivors' long-term quality of life. Patient reported outcome measures (PROMs) are increasingly utilised to evaluate CIPN. However, guidance remains lacking on how to identify fit for purpose PROMs with considerations necessarily differing when used in various research and in-clinic contexts. This study aimed to evaluate evidence about CIPN PROMs measurement properties and propose considerations to optimize CIPN PROM selection for each purpose. METHODS: A systematic review was conducted to identify literature assessing measurement properties of CIPN PROMs. These were evaluated against Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria and International Society for Quality of Life minimum standards. Risk of Bias (RoB) was assessed using the COSMIN RoB checklist. RESULTS: Thirty-nine papers evaluating measurement properties of 13 PROMs were included. The European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy-Induced Peripheral Neuropathy Questionnaire (QLQ-CIPN20) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) were the most commonly investigated PROMs and had the most measurement properties meeting established criteria. CONCLUSION: The use of the QLQ-CIPN20 and FACT/GOG-Ntx to assess CIPN in research settings has the most supporting evidence. However other considerations including study aims, endpoints and target population also factor into PROM selection and need to be considered more often when determining the most suitable outcome measure. Evidence of CIPN PROMs use in clinical practice is limited and their adoption to individual-patient level management requires more evaluation.

Chemotherapy-Induced Peripheral Neurotoxicity in Cancer Survivors: Predictors of Long-Term Patient Outcomes.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major adverse effect of cancer treatment. However, its impact remains poorly understood. This study aimed to investigate the impact associated with CIPN on the lives of cancer survivors. PATIENTS AND METHODS: A volunteer sample of 986 individuals who had received neurotoxic chemotherapy completed an anonymous, cross-sectional survey. Outcomes assessed included CIPN symptoms, pain, neuropathic pain, quality of life (QoL), physical activity, and comorbid health conditions via the Self-Administered Comorbidity Questionnaire. RESULTS: Respondents had a mean age of 58 years (SD, 10.7), and 83.2% were female. Most were treated for breast (58.9%) or colorectal cancer (13.5%); had received docetaxel (32.7%), paclitaxel (31.6%), or oxaliplatin (12.5%); and had completed treatment 3.6 ± 3.5 years previously. We found that 76.5% of respondents reported current CIPN. Respondents reporting severe CIPN had poorer QoL, more comorbidities, and higher body mass index, and more often received multiple neurotoxic chemotherapies than those with mild CIPN. Respondents who completed the survey ≤1 year after completing chemotherapy did not differ in reported CIPN or pain compared with respondents who completed chemotherapy ≥6 years earlier. However, respondents who completed chemotherapy ≥6 years earlier reported better QoL. Multivariable linear regression analyses revealed predictors of CIPN severity as follows: F(7, 874) = 64.67; P<.001; R2 = 0.34, including pain (ß = -0.36; P<.001), burning pain (ß = 0.25; P<.001), sex (male sex associated with greater CIPN: ß = 0.14; P<.001), years since completing chemotherapy (shorter time associated with greater CIPN; ß = -0.10; P<.001), age (ß = 0.80; P=.006), number of comorbid conditions (ß = 0.07; P=.02), and body mass index (ß = 0.07; P=.02). CONCLUSIONS: Respondents with a high CIPN symptom burden experienced poorer general health and QoL. Improvements in CIPN may be more likely soon after treatment. However, improvements in QoL may occur over time in those with chronic symptoms. CIPN seems to have lasting impacts on cancer survivors, and understanding risk factors is important to enable the design of further preventive and therapeutic management strategies.

Clinical assessment of chemotherapy-induced peripheral neuropathy: a discrete choice experiment of patient preferences.

PURPOSE: Up to 40% of cancer patients treated with neurotoxic chemotherapies experience chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is no gold standard assessment tool for CIPN and there is little information in the literature on patient preferences for such assessments. This study aims to address this gap by identifying the features of a CIPN assessment tool that cancer patients value. METHODS: An online discrete choice experiment (DCE) survey of neurotoxic chemotherapy-treated patients was implemented. Respondents completed 8 choice questions each. In each choice question, they chose between two hypothetical CIPN assessment tools, each described by six attributes: impact on quality of life; level of nerve damage detected; questionnaire length; physical tests involved; impact on clinic time; impact on care. RESULTS: The survey was completed by 117 respondents who had a range of cancers of which breast cancer was the most common. Respondents favoured an assessment tool that includes a physical test and that asks about impact on quality of life. Respondents were strongly opposed to clinicians, alone, deciding how the results of a CIPN assessment might influence their care especially their chemotherapy treatment. They were concerned about small changes in their CIPN, independent of clinical relevance. Respondents were willing to add half an hour to the usual clinic time to accommodate the CIPN assessment. CONCLUSION: The findings of this DCE will assist clinicians in choosing an assessment tool for CIPN that is satisfactory to both clinician and patient.

Hemoglobin, Body Mass Index, and Age as Risk Factors for Paclitaxel- and Oxaliplatin-Induced Peripheral Neuropathy.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic cancer treatments including taxanes and platinum agents. Limited knowledge exists of potential prechemotherapy factors associated with CIPN development. Objective: To identify the association of pretreatment blood-based and clinical factors with CIPN persistence in patients who received paclitaxel or oxaliplatin. Design, Setting, and Participants: This cohort study assessed pretreatment blood-based clinical factors and demographic characteristics of 333 patients treated with paclitaxel and oxaliplatin chemotherapy at urban multicenter cancer clinics and academic institutions in Australia between September 2015 and February 2020. Comprehensive neuropathy assessments were undertaken 3 to 12 months posttreatment. Posttreatment CIPN severity was compared with blood-based factors within 30 days prior to commencing chemotherapy. Data were analyzed between March and December 2020. Exposures: Paclitaxel or oxaliplatin chemotherapy. Main Outcomes and Measures: CIPN was measured using composite neurological grading scales, nerve conduction studies, and assessments of fine motor skills (grooved pegboard test), sensory function (grating orientation test and 2-point discrimination), and patient-reported outcomes. Independent samples t tests and Mann-Whitney U tests with post hoc Bonferroni correction were used to compare CIPN between patients according to blood-based factor normative ranges. Linear regression was used to identify blood-based and clinical associations with CIPN development. Results: The study included 333 participants (266 [79.9%] women; median [interquartile range] age, 58 [18] years) who were consecutively recruited and referred (228 treated with paclitaxel, 105 treated with oxaliplatin; 138 [41.4%] with breast cancer, 83 [24.9%] with colorectal cancer). Most participants had grade 1 CIPN or higher (238 [71.5%] participants). Participants with low hemoglobin pretreatment had worse CIPN posttreatment (median [IQR] composite neurological grading scale score, 5 [2-8] vs 4 [1-6]; P = .002; grooved pegboard mean [SD] time, 84.2 [28.7] vs 72.9 [21.1] seconds; P = .002; grating orientation task, 4.8 [2.8] vs 3.9 [1.8] mm; P = .03; 2-point discrimination, 45% vs 28%; P = .01), with no other impairments outside normative ranges associated with CIPN. In the multivariable model, several factors were associated with worse CIPN (F4,315 = 18.6; P < .001; r2 = .19) including for lower hemoglobin (ß = -0.47; 95% CI, -0.73 to -0.21; P < .001), higher body mass index (ß = 0.08; 95% CI, 0.02 to 0.12; P = .007), older age (ß = 0.08; 95% CI, 0.06 to 0.11; P < .001), and female sex (ß = -1.08; 95% CI, -1.76 to -0.16; P = .01). Conclusions and Relevance: The results of this cohort study suggest that participants with low pretreatment hemoglobin, higher body mass index, older age, and female sex were more likely to develop paclitaxel- or oxaliplatin-induced CIPN posttreatment. Future research should investigate prospectively whether these risk factors are associated with a higher incidence of CIPN development.

A double blind, placebo controlled, phase II randomised cross-over trial investigating the use of duloxetine for the treatment of chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of cancer treatment, potentially leading to early cessation of chemotherapy, enduring symptoms and long-lasting disability. Evidence from preclinical and clinical studies suggests that duloxetine, a serotonin-noradrenaline reuptake inhibitor, may be effective in the symptomatic treatment of CIPN. This double blind, placebo controlled, phase II randomised cross-over trial aims to determine whether treatment with duloxetine results in a reduction in chronic neuropathic symptoms experienced as a result of neurotoxic chemotherapy treatment. METHODS/DESIGN: Participants who have received neurotoxic chemotherapy and experience daily symptoms as a consequence of peripheral neuropathy will be randomly allocated to control or experimental group with a 1:1 allocation, stratified by chemotherapy type. The primary endpoint will be patient-reported CIPN symptoms, as assessed via the FACT/GOG-Ntx. As a secondary objective, the trial will investigate whether duloxetine improves neurophysiological parameters and functional status in patients who have received neurotoxic chemotherapy treatment. DISCUSSION: This trial will investigate the effectiveness of duloxetine in reducing neuropathic symptoms following chemotherapy treatment, and aims to provide insight into the mechanisms underlying the symptomatic relief that duloxetine may provide. These results will be informative in advancing clinical knowledge regarding the treatment of CIPN.

An investigation of potential neural correlates of intrusive retrieval of distressing memories.

BACKGROUND AND OBJECTIVES: Despite the prevalence of intrusive memories across psychological disorders, little is known about the neural networks that underpin this form of memory. This study used functional magnetic resonance imaging (fMRI) to identify neural circuits associated with the retrieval of intrusive memories. METHODS: Participants with moderate levels of anxiety (N = 30) underwent a cold pressor task to induce a physiological stress response, after which they viewed 10 neutral and 10 negative film clips. In a method designed to induce intrusive memories, participants then completed an fMRI scan in which they viewed short (2 s) depictions of neutral components from the original film clips. RESULTS: There were no significant differences in activations during intrusion and non-intrusion responses. Exploratory analyses comparing intrusive responses to neutral stimuli found the insula, inferior frontal gyrus, precuneus, right cerebellum and bilateral supplementary motor area were uniquely activated during experience of intrusions (compared to the neutral cue baseline), whereas no significant activations were in response to negative scenes that did not trigger intrusions. LIMITATIONS: This study did not compare the different neural processes implicated in intrusive and intentional emotional memories. The limited intrusions that could be elicited in the scanning environment restricted the number of trials that could be employed. CONCLUSIONS: Although no differences in neural activations were observed between intrusive and non-intrusive responses, the observation of precuneus involvement is consistent with models that propose that intrusive memories are impacted by the extent to which there is contextual integration of the relevant memories.

Self-construal differences in neural responses to negative social cues.

Cultures differ substantially in representations of the self. Whereas individualistic cultural groups emphasize an independent self, reflected in processing biases towards centralized salient objects, collectivistic cultures are oriented towards an interdependent self, attending to contextual associations between visual cues. It is unknown how these perceptual biases may affect brain activity in response to negative social cues. Moreover, while some studies have shown that individual differences in self-construal moderate cultural group comparisons, few have examined self-construal differences separate to culture. To investigate these issues, a final sample of a group of healthy participants high in trait levels of collectivistic self-construal (n=16) and individualistic self-construal (n=19), regardless of cultural background, completed a negative social cue evaluation task designed to engage face/object vs context-specific neural processes whilst undergoing fMRI scanning. Between-group analyses revealed that the collectivistic group exclusively engaged the parahippocampal gyrus (parahippocampal place area) - a region critical to contextual integration - during negative face processing - suggesting compensatory activations when contextual information was missing. The collectivist group also displayed enhanced negative context dependent brain activity involving the left superior occipital gyrus/cuneus and right anterior insula. By contrast, the individualistic group did not engage object or localized face processing regions as predicted, but rather demonstrated heightened appraisal and self-referential activations in medial prefrontal and temporoparietal regions to negative contexts - again suggesting compensatory processes when focal cues were absent. While individualists also appeared more sensitive to negative faces in the scenes, activating the right middle cingulate gyrus, dorsal prefrontal and parietal activations, this activity was observed relative to the scrambled baseline, and given that prefrontal and occipital regions were also engaged to neutral stimuli, may suggest an individualistic pattern to processing all social cues more generally. These findings suggest that individual differences in self-construal may be an important organizing framework facilitating perceptual processes to emotionally salient social cues, beyond the boundary of cultural group comparisons.

Intrusive Memories of Distressing Information: An fMRI Study.

Although intrusive memories are characteristic of many psychological disorders, the neurobiological underpinning of these involuntary recollections are largely unknown. In this study we used functional magentic resonance imaging (fMRI) to identify the neural networks associated with encoding of negative stimuli that are subsequently experienced as intrusive memories. Healthy partipants (N = 42) viewed negative and neutral images during a visual/verbal processing task in an fMRI context. Two days later they were assessed on the Impact of Event Scale for occurrence of intrusive memories of the encoded images. A sub-group of participants who reported significant intrusions (n = 13) demonstrated stronger activation in the amygdala, bilateral ACC and parahippocampal gyrus during verbal encoding relative to a group who reported no intrusions (n = 13). Within-group analyses also revealed that the high intrusion group showed greater activity in the dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus and occipital regions during negative verbal processing compared to neutral verbal processing. These results do not accord with models of intrusions that emphasise visual processing of information at encoding but are consistent with models that highlight the role of inhibitory and suppression processes in the formation of subsequent intrusive memories.

Self-Orientation Modulates the Neural Correlates of Global and Local Processing.

Differences in self-orientation (or "self-construal") may affect how the visual environment is attended, but the neural and cultural mechanisms that drive this remain unclear. Behavioral studies have demonstrated that people from Western backgrounds with predominant individualistic values are perceptually biased towards local-level information; whereas people from non-Western backgrounds that support collectivist values are preferentially focused on contextual and global-level information. In this study, we compared two groups differing in predominant individualistic (N = 15) vs collectivistic (N = 15) self-orientation. Participants completed a global/local perceptual conflict task whilst undergoing functional Magnetic Resonance Imaging (fMRI) scanning. When participants high in individualistic values attended to the global level (ignoring the local level), greater activity was observed in the frontoparietal and cingulo-opercular networks that underpin attentional control, compared to the match (congruent) baseline. Participants high in collectivistic values activated similar attentional control networks o only when directly compared with global processing. This suggests that global interference was stronger than local interference in the conflict task in the collectivistic group. Both groups showed increased activity in dorsolateral prefrontal regions involved in resolving perceptual conflict during heightened distractor interference. The findings suggest that self-orientation may play an important role in driving attention networks to facilitate interaction with the visual environment.