Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: A randomized controlled trial (PAM study).
Authors: Koevoets Emmie , Schagen Sanne B. , de Ruiter Michiel B. , Geerlings Mirjam I , Witlox Lenja , Van Der Wall Elsken , Stuiver Martijn M. , Sonke Gabe S. , Velthuis Miranda , van der Palen Job , Jobsen Jan J. , May Anne Maria , Monninkhof Evelyn M. ,   on behalf of the PAM Study Group
Published: June 2021

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Background: Chemotherapy is associated with cognitive problems. Physical exercise is a promising intervention. We investigated whether exercise improves cognition in chemotherapy-exposed breast cancer (BC) patients 2-4 years after diagnosis. Methods: In the PAM study, we randomized chemotherapy-exposed BC patients with self-reported and test-confirmed cognitive problems to an exercise or control group. The 6-month exercise intervention consisted of 2 hours of supervised aerobic and resistance training and two hours of Nordic/power walking. Memory function measured with the Hopkins Verbal Learning Test-Revised (HVLT-R) was our primary outcome. Further measurements included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognitive complaints (MDASI-MM, EORTC QLQ C-30 cognitive functioning), physical fitness (VO2peak), fatigue (MFI, EORTC fatigue), quality of life (QoL; EORTC), anxiety (HADS) and depression (HADS, PHQ9). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement of ≥5 words. Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. An hypothesis driven but not pre-specified analysis in patients with high baseline EORTC fatigue levels (≥39) was performed. 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 program and physical fitness significantly improved compared to the control patients ( VO2peak1.4 ml/min/kg, 95% CI 0.6; 2.2). No difference in favor of the intervention group was seen on the primary cognitive outcome or other cognitive tests. However, significant beneficial intervention effects were found for self-reported cognition (MDASI-MM Severity (-0.7, -1.2;-0.1)), fatigue (general fatigue (-2.2, -3.3; -1.1), physical fatigue (-3.3, -4.4; -2.2), mental fatigue (-1.0, -2.0; 0.0), reduced motivation (-1.1, -2.0; -0.2) and reduced activity (-2.1, -3.2; -1.1)), QoL (summary score (4.0, 1.2; 6.7), global health status (5.8, 1.1; 10.6), role functioning (7.2, 1.3; 13.1) and social functioning (5.9, 0.2; 11.6)) and depression (PHQ9 (-1.16, -2.19; -0.13)). In high-fatigued patients, exercise did show significant positive effects on objective cognitive function (ACS Reaction Time (-26.8, -52.9; -0.6) and ACS Wordlist Learning (4.4, 0.5; 8.3)). Conclusions: A 6-month exercise intervention did not improve objectively measured cognitive function in chemotherapy-exposed BC patients with cognitive problems. However, self-reported cognitive function, physical fitness, fatigue, QoL and depression did improve. Unplanned analysis indicated a small positive effect of exercise on cognitive functioning in high-fatigued patients. Clinical trial information: NTR6104.