Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study)

Abstract

Background: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis.

Methods: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO_2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors.

Results: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO_2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)].

Conclusions: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Keywords: Aerobic exercise; Breast cancer; Cancer-related cognitive impairment; Cognition; Cognitive complaints; Exercise training; Physical exercise; Physical fitness; Strength exercise.

Fig. 1

Flowchart of inclusion and randomization procedures of the Physical Activity and Memory (PAM) study patients. *Information through social media, pamphlets and by word of mouth. ^#During the COVID-19 pandemic, seven patients completed the exercise program partly at home. The HVLT-R was assessed during video calls instead of face-to-face (n = 13). Less cardiopulmonary exercise tests were performed (missing: n = 13)

Fig. 2

Exercise intervention effects on cognitive functioning in breast cancer patients. HVLT-R, Hopkins Verbal Learning Test-Revised; MDASI-MM, MD Anderson Symptom Inventory for multiple myeloma. Reaction Time in ms is divided by 10. ^†The treatment effect is the regression coefficient of a linear regression analysis adjusted for baseline cognitive test score, age, and endocrine therapy. Tests/questionnaires for which a higher score indicated worse performance/more symptoms were inverted [Reaction Time, Connecting the Dots (I & II), Place the Beads, Fill the Grid, and MDASI-MM (Severity and Interference)]. Therefore, a positive score indicates a beneficial effect of the intervention. ^‡Effect Sizes (ES) were calculated by dividing Beta by the pooled SD at baseline, with positive ESs meaning a beneficial effect of the intervention on a specific outcome. ESs < 0.2 indicate “no difference,” ESs between 0.2 and 0.5 indicate “small differences,” ESs between 0.5 and 0.8 indicate “medium differences,” and ESs ≥ 0.8 indicate “large differences” [50]. An ES of 0.5 or higher was considered clinically relevant [51]

Fig. 3

Exercise intervention effects on cognitive functioning in highly fatigued breast cancer patients. HVLT-R, Hopkins Verbal Learning Test-Revised; MDASI-MM, MD Anderson Symptom Inventory for multiple myeloma. Reaction Time in ms is divided by 10. ^†The treatment effect is the regression coefficient of a linear regression analysis adjusted for baseline cognitive test score, age, and endocrine therapy. Tests/questionnaires for which a higher score indicated worse performance/more symptoms were inverted [Reaction Time, Connecting the Dots (I and II), Place the Beads, Fill the Grid, and MDASI-MM (Severity and Interference)]. Therefore, a positive score indicates a beneficial effect of the intervention. ^‡Effect Sizes (ES) were calculated by dividing Beta by the pooled SD at baseline, with positive ESs meaning a beneficial effect of the intervention on a specific outcome. ESs < 0.2 indicate “no difference,” ESs between 0.2 and 0.5 indicate “small differences,” ESs between 0.5 and 0.8 indicate “medium differences,” and ESs ≥ 0.8 indicate “large differences” [50]. An ES of 0.5 or higher was considered clinically relevant [51]

Fig. 4

Exercise intervention effects on patient-reported outcomes. MFI Multidimensional Fatigue Inventory, EORTC European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, PHQ-9 Patient Health Questionnaire-9, HADS hospital anxiety and depression scale. ^†The treatment effect is the regression coefficient of a linear regression analysis adjusted for baseline scores, age, and endocrine therapy. Questionnaires for which a higher score indicated worse functioning/more symptoms were inverted (MFI subscales, EORTC Fatigue, EORTC Pain, EORTC Insomnia, PHQ-9, and HADS Depression and Anxiety). Therefore, a positive score indicates a beneficial effect of the intervention. ^‡Effect Sizes (ES) were calculated by dividing Beta by the pooled SD at baseline, with positive ESs meaning a beneficial effect of the intervention on a specific outcome. ESs < 0.2 indicate “no difference,” ESs between 0.2 and 0.5 indicate “small differences,” ESs between 0.5 and 0.8 indicate “medium differences,” and ESs ≥ 0.8 indicate “large differences” [50]. An ES of 0.5 or higher was considered clinically relevant [51]