Longitudinal Changes in Cognitive Function in a Nationwide Cohort Study of Patients With Lymphoma Treated With Chemotherapy

Abstract

Background: Cancer-related cognitive decline (CRCD) is an important clinical problem, but limited research exists on assessment of cognitive function in patients with lymphoma.

Methods: The overall objective of this nationwide, prospective, observational study conducted in the National Cancer Institute Community Clinical Oncology Research Program (NCORP) was to assess changes in memory, attention, and executive function in patients with lymphoma from pre- (A1) to postchemotherapy (A2) and to 6 months postchemotherapy (A3). Individuals without cancer served as noncancer controls, paired to patients by age and sex, and assessed at the same time-equivalent points. Longitudinal linear mixed models (LMM) including A1, A2, and A3 and adjusting for age, education, race, sex, cognitive reserve score, baseline anxiety, and depressive symptoms were fit. We assessed changes in patients compared with control participants without cancer and assessed differences in cognitive function in those patients with Hodgkin vs non-Hodgkin disease and by disease subtype. All statistical tests were 2-sided.

Results: Patients with lymphoma (n = 248) and participants without cancer serving as controls (n = 212) were recruited from 19 NCORP sites. From pre- to postchemotherapy and from prechemotherapy to 6 months follow-up, patients reported more cognitive problems over time compared with controls (Functional Assessment of Cancer-Therapy-Cognitive Function [FACT-Cog] perceived cognitive impairment effect size (ES) = 0.83 and 0.84 for A1 to A2 and A1 to A3, respectively; P < .001; single-item cognitive symptoms ES range = 0.55 to 0.70 inclusive of A1 to A2 and A1 to A3; P < .001); the complaints were more pronounced in women with lymphoma compared with men with lymphoma (FACT-Cog Perceived Cognitive Impairment (PCI) score group-by-time-by-sex interaction, P = .007). Patients with lymphoma also performed statistically significantly less well on tests of verbal memory and delayed recall, attention and executive function, and telephone-based category fluency.

Conclusion: Patients with lymphoma experience worse patient-reported and objectively assessed cognitive function from prechemotherapy to 6-month follow-up compared with age- and sex-paired controls without cancer assessed at similar time intervals.

Figure 1.

Participant flowchart. A = assessment.

Figure 2.

Effect sizes for changes on cognitive measures in patients compared to controls. To determine the effect size (ES), we used a Cohen d approach, where the effect estimates (β) were divided by the estimated standard deviation of the population (ie, all subjects at baseline). Statistically significant effect sizes (after FDR adjustment) are expressed as larger circles for assessment 1 (A1) to assessment 2 (A2) and larger triangles for assessment 1 (A1) to assessment 3 (A3). CANTAB = Cambridge Neuropsychological Test Automated Battery; COWA = Controlled Oral Word Association Test; DMS = delayed match to sample; FACT-Cog = Functional Assessment of Cancer-Therapy-Cognitive Function; HVLT-R = Hopkins Verbal Learning and Memory Test-Revised; RAVLT = Rey Auditory Verbal Learning Test; RVP = Rapid Visual Processing; TMT = Trail Making Test; VRM = verbal recognition memory.

Figure 3.

Fact-Cog self-report scores in women and men with lymphoma and controls. Assessments (A) are prechemotherapy (A1), postchemotherapy (A2), and 6 months following chemotherapy (A3; or time equivalent for control participants). Smaller values imply greater perceived cognitive impairment. Mean adjusted scores on each test and the corresponding 95% confidence intervals are presented for A1 (0 months; approximately within 7 days prior to chemo), A2 (approximately 3.3 months from A1; postchemotherapy), and A3 (approximately 9.3 months from A1; 6-month follow-up) in panels A and C (stratified by patients with lymphoma receiving chemotherapy (dashed blue line) vs control participants (solid red line)) and panels B and D (additionally stratified by female vs male). Panels A and B include adjusted PCI scores, and panels C and D include adjusted total scores. Unadjusted plots are provided in Supplementary Figure 1 (available online). FACT-Cog = Functional Assessment of Cancer-Therapy-Cognitive Function.

Figure 4.

Prevalence of overall perceived cognitive impairment on the FACT-Cog PCI score based on clinically important differences from pre- to postchemotherapy and prechemotherapy to 6 months following completion of chemotherapy in women (A and B) and men (C and D). “Better” is defined as a minimal clinically important difference (based on ½ SD of controls at baseline) increase of 6.19 or more in the FACT-Cog, and “worse” is defined as a decrease of 6.19 or more. The y axis represents the percentage of participants meeting each threshold or who stayed the same. FACT-Cog = Functional Assessment of Cancer Therapy-Cognitive Function; PCI = perceived cognitive impairment. Blue bars = lymphoma and orange bars = control.