Cognitive Symptoms Across Diverse Cancers

This cross-sectional study describes the prevalence and severity of cognitive symptoms self-reported by outpatient adults with different cancer diagnoses.


Introduction
Cognitive symptoms are distressing for many individuals with cancer, affecting emotional, social, and functional well-being. 1,2Common cognitive symptoms in this population include memory, attention, concentration, processing speed, and executive functioning difficulties.Although the relationship between self-reported cognitive functioning and neurocognitive test performance can vary, patients experiencing difficulties describe problems with adherence to self-care regimens, engagement in desired activities, and everyday tasks.Patient-reported difficulties in treatment and follow-up clinics can be the impetus for specialized assessment and supportive care interventions.Cognitive symptoms affect up to 75% of patients during active treatment and persist for some survivors for months to years afterward. 3,4However, supportive care for cognitive symptoms remains an unmet need among patients with diverse cancer diagnoses. 5,6e explanation for this practice gap is the relatively narrow scope of evidence to date, which has focused predominantly on patients with central nervous system (CNS) and breast cancers. 3,7,8tients with primary or metastatic CNS disease may be particularly at risk for cognitive impairment associated with tumor location and treatments. 9,10In breast cancer, cognitive symptoms have been associated with chemotherapy, 11,12 with evidence that anthracyclines may pose greater risk. 139][20] In addition, research on selected cancer types used varied measurement tools and approaches to identify demographics (eg, age and sex), clinical factors (eg, time since treatment and treatment type), and co-occurring symptoms (eg, fatigue and depression) associated with cognitive impairment. 15,18Whether these associations are stable across cancer types is unclear, further complicating the implementation of system-level assessment and management strategies.
In an anonymous online survey of 3108 US cancer survivors who were recruited through social media, 21 46% of participants experienced cognitive symptoms, with high rates of symptoms among those with CNS (81%) and breast (58%) cancers as well as non-Hodgkin lymphoma (50%), Hodgkin lymphoma (50%), colorectal cancer (46%), and head and neck cancer (44%).In the survey, cognitive symptoms were associated with having received chemotherapy and concurrent report of depressive symptoms. 21Another study investigated cognitive symptoms among 6786 volunteer participants in the Dutch PROFILES (Patient Reported Outcomes Following Initial Treatment and Long-term Evaluation of Survivorship) cancer registry and healthy matched controls. 22With the exception of survivors with melanoma and basal cell or squamous cell carcinomas, survivors reported lower cognitive functioning compared with controls, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) Cognitive Functioning subscale.Across the sample, younger age (<50 years) was associated with poorer cognitive functioning, and clinically important cognitive symptoms were associated with greater fatigue and depression. 22While existing evidence suggests the need for health services to address cognitive symptoms, the research contexts in which those data were collected differ from clinical contexts in which such services would be developed and implemented.The present study investigated cognitive symptoms data obtained through an institutional routine patient-reported outcomes-based symptom screening program in an outpatient clinical setting.Using these clinical data, we aimed to (1) characterize the frequency and severity of cognitive symptoms and (2) identify demographic and

Study Design
The University Health Network and University of Toronto Research Ethics Boards approved this retrospective cross-sectional study, which was conducted according to the Declaration of Helsinki. 23 it was impracticable to seek informed consent from individuals in this retrospective study, University Health Network Research Ethics Board waived the informed consent requirement.We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. 24e DART In 2010, Princess Margaret Cancer Centre in Toronto, Ontario, Canada, established the Distress Assessment and Response Tool (DART) to facilitate routine symptom screening as part of standard clinical care. 25The DART is a computerized survey designed to identify physical, emotional, and practical concerns using validated patient-reported outcome measures and individual items, the combination of which are ascertained at the scheduled visit through embedded computer adaptive testing algorithms. 25At the time of the study, patients completed the DART on a touchscreen computer in the waiting room; reports are provided to the clinic team to facilitate further assessment and intervention.At 3-month intervals, the DART includes a screening question regarding the need for psychosocial support for social difficulties: In the past month have you had concerns in the following areas that you want to discuss with a member of our health care team: family life and social activities, eg, communication, isolation, trouble concentrating, plans to have a family, sexual matters?
A yes response triggers additional questions, including an item regarding cognitive symptoms.In 2013, the DART was implemented across all ambulatory cancer clinics within Princess Margaret Cancer Centre.

Participants
We identified patients who completed the DART between January 1, 2013, and December 31, 2019, endorsed interest in receiving psychosocial support from a health care team member for social difficulties, and responded to the cognitive symptom item.For these respondents, linked clinical data from the institutional registry were retrieved to confirm cancer diagnosis and other medical and clinical characteristics concurrent with the time of response to the cognitive symptom question.If patients responded to the cognitive symptom item more than once, the most recent response was used.We excluded patients for whom a cancer diagnosis could not be confirmed, whose registry records were unavailable, or with a history of multiple primary cancers to enable attribution of characteristics (eg, treatment) to individual cancer types.

Variables
An adapted version of the Self and Others subscale of the Social Difficulties Inventory-21 26,27 was modified to include the following question regarding cognitive symptoms: Have you had any difficulty with thinking abilities, such as concentration, memory or word finding?The wording of this item was designed to align with the Patient-Reported Outcomes Measurement Information System 0][31] Response categories to this item included no difficulty, a little, quite a bit, and very much.For this analysis, we defined any presence of cognitive symptoms as a response of a little, quite a bit, or very much; moderate to severe cognitive symptoms were considered present from the response of quite a bit or very much.

Statistical Analysis
The presence and severity of cognitive symptoms across different cancer types, demographics, and medical characteristics were described using frequencies and proportions.To identify risk factors associated with moderate to severe cognitive symptoms, we used generalized linear mixed modeling for binary outcomes across the total sample, with cancer type as a random effect to account for within-site similarity.First, we used bivariate analyses to assess the associations between moderate to severe cognitive symptoms and the following variables: age at time of survey, sex, first-line treatments received (surgery, radiotherapy, chemotherapy, hormonal therapy, or biological response modifiers), metastatic disease at diagnosis, cancer recurrence involving the CNS, and time since primary cancer diagnosis.Second, we simultaneously entered variables associated with moderate to severe cognitive symptoms in the multivariable model and reduced them to generate the most parsimonious model.
All P values were 2-sided, with P < .05considered statistically significant.Analyses were conducted from April 2020 to June 2024 using SAS 9.4 (SAS Institute Inc).

Sample Characteristics
A total of 5078 individuals responded to the cognitive symptoms item in the DART and had a corresponding record in the cancer registry.other patient-reported outcome measures, and the need to further characterize cognitive outcomes and risk factors in understudied adult cancer populations. 35These findings may inform the development of health services from an organizational perspective and offer hypothesis-generating data for future studies conducted within specific populations.a Percentages for missing data were calculated from complete data (N = 5078) to show the proportion of missing, whereas all other percentages were calculated excluding the missing data to add up to 100%.
b High cognitive difficulty (from response of quite a bit or very much).
c Includes distant-other, local, regional, and unknown.
d Patients with primary brain cancers were not considered to have metastatic disease.b Includes distant-other, local, regional, and unknown.
Cognitive symptoms were most severe in patients with CNS cancers, and moderate to severe cognitive symptoms were associated with primary CNS cancer progression or metastasis.9][40][41][42][43] However, the presence and severity of symptoms among these patients vary. 44In this study, we underscored the degree to which patients with brain cancers seeking psychosocial support required support for cognitive issues, and how this may compare across patients with other cancer types.The relatively high prevalence of cognitive symptoms across patients with non-CNS cancers seeking psychosocial support and the similarity of associated factors warrant future investigation.Metastatic disease at the time of diagnosis was associated with lower odds of moderate to severe cognitive difficulties among people seeking psychosocial support.Individuals with metastatic cancer experience many moderate to severe concerns, particularly regarding worsening disease and the future, 45 but may also express hope and reflect on favorable aspects of their lives within the context of terminal illness. 46Such experiences may contribute to the concerns reported when seeking psychosocial support.
Severity of concurrent ESAS symptoms were associated with reports of moderate to severe cognitive symptoms.Tiredness and depression, and to a lesser degree drowsiness and anxiety, were all independently associated with increased odds of moderate to severe cognitive symptoms in the total sample and in each of the 12 cancer types.Associations of cognitive symptoms with fatigue and emotional distress have been reported in several cancer populations, 21,22,[47][48][49][50] with speculations that their co-occurrence may constitute a symptom cluster with shared biological mechanisms, such as inflammation. 51,52We also found an association with shortness of breath in the overall sample and in breast and head and neck cancers.We were unable to identify whether the associated factors were parallel outcomes from cancer and treatment; causative, with cognitive decline playing a role in other factors or in the opposite direction, or some combination; or a self-reported halo, 53 a tendency to generally rate any domain throughout all self-reported measures as more unfavorable or favorable. 51,52However, taken together, these findings suggest that in addition to psychoeducation and self-management strategies focusing on cognitive symptoms, interventions promoting management of concurrent symptoms, such as fatigue and emotional distress, may be beneficial. 8,54ceiving chemotherapy as a first-line treatment was associated with moderate to severe cognitive symptoms.The association between chemotherapy and cognitive symptoms in cancer has been consistently demonstrated, 12,15,55 with hypothesized mechanisms underlying oxidative stress and inflammation, among others. 56,570][61] In a systematic review of longitudinal studies in breast cancer, cognitive decline after treatment was generally greater in patients undergoing chemotherapy compared with those not receiving chemotherapy, but cognitive decline was not exclusive to that group. 12,62Different treatments, such as radiotherapy, hormonal therapy, immunotherapy, and/or other targeted therapy, may affect cognition in subgroups of patients that we may not have captured, such as patients with head and neck cancer who receive incidental brain radiation and are at greater risk for cognitive impairments. 14,35Adding cognitive outcomes to emerging clinical trials can accelerate understanding of the potential role of novel treatment regimens, as has been recommended. 19e risk of moderate to severe cognitive symptoms increased among female patients in this sample, which would not necessarily be expected given that there are no sex-based differences in subjective cognitive decline in healthy adults at or over age 45 years. 63This finding may be partly explained by the elevated rates of moderate to severe cognitive symptoms in breast cancer, but female sex was also a significant factor in moderate to severe cognitive symptoms in patients with hematological cancers.This finding may be attributed to treatment-induced menopause or sex differences in treatment toxic effects. 64We lacked data on gender identity, which is relevant since symptom reporting is also affected by social factors associated with gender identity. 65Distinguishing the complex sex-and gender identity-based differences in cancer-related symptoms remains an understudied area of research.
In the multivariable analysis, age was not a significant risk factor for cognitive symptoms.
However, because the experience and needs related to symptom management may vary across the life span, further research to characterize the patterns and outcomes of cognitive symptoms by developmental stage can inform effective age-appropriate interventions.

Limitations
Limitations of this study include its retrospective cross-sectional design and lack of prospective data regarding other factors potentially associated with cognitive symptoms.Additionally, details on the treatments received after the primary treatment regimen were unavailable.This analysis was limited to patients who endorsed interest in receiving psychosocial support for social difficulties during routine symptom screening.Therefore, we did not have information on cognitive symptoms for those who declined psychosocial support.The prescreening questions used may account for the slightly higher prevalence of cognitive symptoms reported in this study compared with other published studies. 21Nonetheless, we have no reason to speculate that this method would affect the relative prevalence of cognitive symptoms across the diverse cancer types in the sample.While the findings suggest that cognitive issues are common among patients seeking psychosocial support, it is unknown whether the findings generalize to patients who do not complete the DART in clinic or do not endorse social difficulties requiring psychosocial support.

Conclusions
In this cross-sectional study of outpatient adults with cancer requesting psychosocial support on routine symptom screening, cognitive symptoms were frequently reported.Higher severity of cognitive symptoms was consistently associated with higher symptom burden.A common limitation of the prior literature was the applicability in clinical settings vs in research trials.Our findings advance extant literature that was developed from research context by reinforcing it with a clinical dataset, supporting clinical applicability.When cognitive symptoms are not acknowledged and/or addressed by the care team, patients experience distress, fear, and stigma and face barriers to appropriate supportive care. 1,2,66Our findings provide clinicians with the prevalence of cognitive symptoms in a wide range of cancer types, which could be used to inform decision-making regarding access to cognitive screening, assessment, and supportive care in outpatient oncology clinics.In addition, the findings signal the need for expanded research to understand site-specific factors associated with cognitive symptoms.8][69][70] Extracted data included date of birth; sex; primary cancer type (with International Classification of Diseases for Oncology, Third Edition 34 codes); date of primary cancer diagnosis; presence of metastatic disease at the time of diagnosis; and treatment modalities used in the first course or initial management of disease, including surgery, radiotherapy, chemotherapy, hormonal therapy (eg, tamoxifen and dexamethasone), and/or biological response modifiers (eg, trastuzumab and rituximab).Cancer recurrence was categorized as involving the CNS (brain metastases or progression of primary CNS cancer), not involving the CNS (non-CNS distant metastases or local or regional to the non-CNS primary cancer site), or none.The 12 cancer types in the sample were brain or CNS, breast, gastrointestinal, genitourinary, gynecological, head and neck, hematological, lung and bronchus, melanoma, sarcoma, thyroid, and all other cancers.

Table 2 .
Frequency and Severity of Cognitive Difficulty by Cancer Type a a Based on responses to the question of "During the past month, have you had any difficulty with thinking abilities, such as concentration, memory, and word finding?" b From response of a little, quite a bit, or very much.cFromresponse of quite a bit or very much.dAll other cancers include trachea; thymus; heart, mediastinum, or pleura; other and ill-defined types of the respiratory system and intrathoracic organs; selected skin, peripheral, and autonomic nervous system; retroperitoneum and peritoneum; and placenta.

Table 4
). Moderate to severe cognitive symptoms were not associated with age at time of survey or time since diagnosis.eTable4 in Supplement 1 provides additional details.Factors Associated

With Moderate to Severe Cognitive Symptoms in Individual Cancer Type
The consistency of cognitive risk factors across individual cancer types was explored through post hoc stratified analyses.In each of the 12 cancer types, the multivariable model was replicated and a reduced parsimonious model was generated based on statistically significant factors.Sex was omitted from the model for breast and gynecological cancer groups, and CNS-involved recurrence was omitted for brain or CNS cancer, as all cases had documented recurrence involving the CNS.In all disease types, moderate to severe cognitive symptoms were consistently associated with ESAS symptom severity, especially depression (ORs ranging from 1.81 [95% CI, 1.11-2.97]forhematological cancer to 4.04 [95% CI, 2.57-6.36]forgynecological cancer) and tiredness (ORs ranging from 1.66 [95% CI, 1.17-2.36]forbreast cancer to 5.36 [95% CI, 1.67-17.28]forthyroid cancer).Moderate to severe cognitive symptoms were also associated with shortness of breath severity in 3 of the cancer groups: head and neck (1.81; 95% CI, 1.13-2.90),breast(2.54; 95% CI, 1.67-3.85),andall other cancers (2.06; 95% CI, 1.18-3.62)(eTable5 in Supplement 1).In some cancer types, some cancer and demographic factors remained associated with cognitive symptom severity even after controlling for ESAS symptom severity.These factors included first-line chemotherapy in breast and hematological cancers, recurrence in gynecological cancers, older age in brain or CNS cancers, and female sex in hematological and other cancers (eTable 5 in Supplement 1).least 60% of participants reporting cognitive symptoms and at least 20% reporting moderate to severe cognitive symptoms.By characterizing cognitive symptoms in a large clinical dataset assessed similarly across a breadth of diverse cancer types, the findings extend previous work using volunteer participants or focusing on single cancer types.Results of this study highlight the pervasiveness of cognitive symptoms in patients with cancer seeking psychosocial support, the associations with

Table 3 .
Bivariate Analysis of Moderate to Severe Cognitive Symptoms

Table 3 .
Bivariate Analysis of Moderate to Severe Cognitive Symptoms (continued)

Table 4 .
Multivariable Analysis of Moderate to Severe Cognitive Symptoms Continued evaluation of the potential role of such interventions in other cancer sites is warranted.Bivariate Analysis of Moderate to Severe Cognitive Symptoms (Age, Time Since Diagnosis, and Symptoms as Continuous Variables) eTable 4. Initial Multivariable Model Including All Variables of Interest to Model Moderate to Severe Cognitive Symptoms eTable 5. Post-Hoc Reduced Multivariable Analyses of Moderate to Severe Cognitive Symptoms by Cancer Type eTable 3.